Curriculum vitae

CARLOS CARDONA LLURIÁ

DATOS PERSONALES

Barcelona, 13 de Marzo de 1959
Idiomas: Inglés, Español y Catalán

FORMACIÓN

• Master en Ciencia (Inmunología Tumoral) University of Birmingham (Gran Bretaña) 1986-1988

• Licenciado en Medicina y Cirugía por la Universidad Autónoma de Barcelona (España) 1976-1985

• Bachillerato y COU: Colegio San Ignacio (Jesuitas), Barcelona, España

EXPERIENCIA LABORAL

2006-Presente Fundador de A-Z Physicians Directory SL (MediRank), Barcelona, España

2002-Presente Fundador de Effiloop Alerts SL, Barcelona, España

1998-2001 Científico en el Hope Heart Institute & Providence Hospital, Seattle, USA

1998-1999 Científico invitado en la University of Washington, Seattle, USA

1995-2003 Fundador de MedVis Consulting, Seattle, USA

1991-1994 Investigador asociado. Fred Hutchinson Cancer Research Center, Seattle, USA.

1988-1992 Investigador & Doctoral Fellow; Dept. Clinical Oncology and Radiotherapeutics, M.R.C., Cambridge University, (Gran Bretaña)

1986-1988 Estudiante de un Master en Ciencia en el Dept. de Inmunología, University of Birmingham (Gran Bretaña)

1985-1986 Soldado médico (Servicio militar), Barcelona, España

1976-1985 Estudiante de Medicina en la Univ. Autónoma de Barcelona, España

ÁREAS DE EXPERIENCIA Y HABILIDADES

MÉDICO:

Medicina personalizada. En busca de todas las posibilidades terapéuticas.

CIENTÍFICO:

• Especialidades médicas de interés:

      o Oncología molecular
      o Enfermedades cardiovasculares
      o Inmunología
      o Virología

• Temática:

      o Inducción del sarcoma de Kaposi vía la inducción del virus KSH-8 en pacientes con SIDA y el cooperativismo viral. Oncogénesis-mutagénesis.
      o Oncogenes y genes de tumors supresores.
      o Proceso metastásico.
      o Alteración de la resistencia a multi-fármacos, mecanismos de radioresistencia en cancerología.
      o Tumores con origen neuroectodermal y tumores hematológicos.
      o Marcadores tumorales séricos.
      o Factores de crecimiento, neuropéptidos como agentes reguladores del crecimiento celular.
      o Unión molecular con el receptor y el proceso endocítico.
      o Fenómeno del crecimiento y diferenciación celular.
      o Identificación de las secuencias de los factores de crecimiento de unión en la estructura molecular de las  proteínas de matriz y su relevancia y efectos sinergísticos en el proceso de la curación de las heridas.
      o Arterioesclerosis y angiogénesis.

• Descubrimientos más relevantes:

      o Descubridor del receptor de la Phyllolitorina mediante un elegante combinación de flujos de calcio intracelular y competición molecular por la máxima afinidad del receptor con el péptido de la liberación de Gastrina y la Neuromedina B.
      o Giro paradigmático sobre la habilidad sintética y procesamiento de células no neuroendocrinas sobre los neuropéptidos.
      o Addendum sobre la teoría del doble golpe oncogéncio para el desarrollo tumoral mediante la co-infección de un virus con la habilidad de alterar el circuito de sus propias citocinas. Una simple mutación es suficiente para el desarrollo de la maquinaria oncogénica unida a la estimulación oncogénica vírica particular.
      o Descubrimiento de un marcador tumoral específico para tumores neuroendocrinos. Una proteína de 28.000 Dalton de peso molecular cuya trascendencia recala en la detección temprana de los tumores de pulmón de célula pequeña.

• Técnicas:

      o Biología celular
      o Bioquímica
      o Biología molecular

INVENTOR:

• Prestigio: Un nuevo modelo matemático para determinar el valor de conceptos jerárquicos.
• Desarrollo del diccionario biomédico Inglés/Castellano más grande del mundo con 26.000 conceptos médicos

MINADOR SINTÁCTICO:

• Producción de bibliotecas inteligentes y eficaces.
• Producción de rankings médicos.
• Desarrollo de un sistema de retroalimentación sobre los nuevos conceptos en bases de datos jerárquicas.
• Análisis sintáctico para entender el lenguaje natural. Alteración de estructura metafórica sobre la lógica clásica.
• Minimización conceptual sobre una gramática sintáctica estructural.
• Estructura del proceso creativo y desarrollo de nuevas habilidades creativas. Estudio sobre el proceso casual y el puzle de la lógica borrosa con cambios de rama radicales.
• Pensamiento retrógrado. Estudio del fenómeno de reconvertir premisas circunstanciales y sus excepciones. Un nuevo y más rápido sistema para entender fenómenos naturales e inducir giros paradigmáticos.
• Análisis teórico sobre los aspectos clasificatorios y razonamiento sobre las hipótesis.

MAESTRO Y CONFERENCIANTE:

• Cursos de oncología, enfermedades cardiovasculares, método científico, escritura científica.
• Capacidad para entender y explicar temas de ciencia clínica y ciencia básica a cualquier tipo de audiencia.

CONSULTOR:

• Desarrollo de un proyecto para la promoción del Hope Heart Institute. Atrajo 10 millones de dólares.
• Maximización de la vida en tumores con mal pronóstico. En búsqueda de nuevas alternativas
• Desarrollo de un centro de investigación sobre el cáncer exitoso. Componentes teóricos.
• Desarrollo programas de investigación biomédica. Un centro de desarrollo de nuevas empresas.
• Creación de una estrategia para el desarrollo de programas de I+D basado sobre la base del conocimiento desarrollado por otros. Elección de los proyectos más maduros y viables.
• Creación de un portafolio de licencias para la industria farmacéutica y la identificación de socios estables. Asociaciones con empresas de biotecnología con sentido común. Distinción entre la biotecs sensatas de las sin sentido.

PREMIOS

Fellowship de la Comunidad Europea Contra el Cáncer

PUBLICACIONES

Temas: Tumores neuroendocrinos. Marcadores tumorales. Leucemias. Neuropéptidos como reguladores del crecimiento celular. Factores de crecimiento y sus receptores. Fenómenos del crecimiento y diferenciación celular. Proteínas de la matriz extracelular. Mecanismo de señalización celular. Arteriosclerosis. Curación de heridas. Angiogénesis.

Novel Vascular Endothelial Growth Factor Binding Domains of Fibronectin Enhance Vascular Endothelial Growth Factor Biological Activity.
Errol S. Wijelath, Jacqueline Murray, Salman Rahman, Yatin Patel, Atsushi Ishida, Kurt Strand, Salim Aziz, Carlos Cardona, William P. Hammond, Geoffrey F. Savidge, Shahin Rafii, Michael Sobel
Circulation Research. 2002 Jul 12;91(1):25-31.
Abstract
Interactions between integrins and growth factor receptors play a critical role in the development and healing of the vasculature. This study mapped two binding domains on fibronectin (FN) that modulate the activity of the angiogenic factor, vascular endothelial growth factor (VEGF). Using solid-phase assays and surface plasmon resonance analysis, we identified two novel VEGF binding domains within the N- and C-terminus of the FN molecule. Native FN bound to VEGF enhanced endothelial cell migration and mitogen-activated protein (MAP) kinase activity, but FN that is devoid of the VEGF binding domains failed to do so. Coprecipitation studies confirmed a direct physical association between VEGF receptor-2 (Flk-1) and the FN integrin, α5β1, which required intact FN because FN fragments lacking the VEGF binding domains failed to support receptor association. Thrombin-activated platelets released intact VEGF/FN complexes, which stimulated endothelial cell migration and could be inhibited by soluble high affinity VEGF receptor 1 and antibodies to α5β1 integrin. This study demonstrates that FN is potentially a physiological cofactor for VEGF and provides insights into mechanisms by which growth factor receptors and integrins cooperate to influence cellular behavior.

 

Induction of the urokinase plasminogen activator system by oncostatin M promotes endothelial migration.
Strand K, Murray J, Aziz S, Ishida A, Rahman S, Patel Y, Cardona C, Hammond WP, Savidge G, Wijelath ES.
Journal of Cellular Biochemistry. 2000 Aug 2;79(2):239-48.
Abstract
Oncostatin M (OSM) is an inflammatory cytokine produced by activated macrophages and T-lymphocytes. We have previously demonstrated that OSM-induced endothelial cell migration, unlike endothelial cell proliferation and spindle formation, is independent of basic fibroblast growth factor expression (Wijelath et al. [1997] J. Cell. Sci. 110:871–879). To better understand the mechanism of OSM-induced endothelial cell migration, this study examined the potential role of the plasminogen activator system in promoting OSM mediated endothelial cell migration. OSM stimulated increased mRNA levels of urokinase-plasminogen activator (uPA) and urokinase-plasminogen activator receptor (uPAR) in a time and dose-dependent manner. Transcriptional run-off and mRNA stability analysis demonstrated that the increase in uPA and uPAR mRNA levels was due to both increased gene transcription and mRNA stability. The increase in mRNA correlated with increased protein levels of both uPA and uPAR. This increase was reflected in elevated levels of membrane-bound plasmin activity. OSM-induced endothelial cell migration was only partially dependent on plasmin activity since incubating endothelial cells without plasminogen or, in the presence of aprotinin, resulted in suppression of endothelial cell migration, indicating that OSM promoted endothelial cell migration through both a plasmin-dependent and -independent mechanism. Our results imply a role for OSM in promoting endothelial cell migration via a plasmin-dependent pathway and a uPAR-mediated pathway. Together, these and other recent studies support a role for OSM in modulating the different phases of angiogenesis.

 

Characterization of ligand binding and processing by gastrin-releasing peptide receptors in a small-cell lung cancer cell line.
C Cardona, N M Bleehen, and J G Reeve
Biochemical Journal. 1992 January 1; 281(Pt 1): 115–120.
Abstract
The ligand-binding properties of the gastrin-releasing peptide (GRP) receptor and the cellular processing of GRP have been studied in the small-cell lung cancer (SCLC) cell line COR-L42. Scatchard analysis of GRP receptor expression indicated a single class of high-affinity receptors (Kd 1.5 nM) and approx. 6700 receptors/cell. GRP bound to its receptor with a Ki of 2.4 nM. The bombesin-related peptides neuromedin B (NMB) and phyllolitorin also bound to GRP receptors with Ki values of 22.7 and 59.1 nM respectively. Binding of 125I-GRP to COR-L42 cells increased rapidly at 37 degrees, achieved a maximum at 10 min and declined rapidly thereafter. At 4 degrees C, maximum binding was achieved at 30 min and the subsequent decline in cell-associated radioactivity was slower than that seen at 37 degrees C. Acid/salt extraction, to separate surface-bound ligand from internalized GRP, indicated that after receptor binding 125I-GRP was rapidly internalized. To determine the pathway of 125I-GRP degradation, binding studies were carried out with the lysosomotropic agent chloroquine (5 mM), and with phosphoramidon (10 microM), an inhibitor of the membrane-bound enzyme (EC 3.4.24.11). Both agents markedly inhibited the degradation of GRP, indicating that this process involves a lysosomal pathway and a phosphoramidon-sensitive pathway, possibly involving the EC 3.4.24.11 enzyme. GRP receptor down-regulation was observed following a 10 min exposure to 100 nM-GRP. With longer pretreatment times the number of binding sites recovered to 80% of control values. Treatment with 5 mM-chloroquine plus GRP or cycloheximide (10 micrograms/ml) plus GRP demonstrated that the majority of GRP receptors are recycled. NMB and phyllolitorin pretreatment did not influence the subsequent binding of 125I-GRP, suggesting that these peptides do not down-regulate GRP receptors.

 

Production of neuromedin B and neuromedin B gene expression in human lung tumor cell lines.
Cardona C, Rabbitts PH, Spindel ER, Ghatei MA, Bleehen NM, Bloom SR, Reeve JG.
Cancer Research. 1991 Oct 1;51(19):5205-11.
Abstract
Gastrin-releasing peptide (GRP), a mammalian bombesin-like peptide, has been shown to be an important autocrine growth factor for small cell lung cancer (SCLC). However, not all SCLC cell lines express the GRP gene or respond mitogenically to GRP stimulation, suggesting the existence of other autocrine pathways in this tumor. Neuromedin B (NMB), the mammalian counterpart of amphibian ranatensin, has been shown to be a mitogen for SCLC cell lines in vitro. To determine whether NMB is a potential autocrine growth factor for lung tumors, NMB gene expression, peptide synthesis, and secretion have been investigated in a panel of SCLC and non-SCLC (NSCLC) cell lines. Northern blot analysis and enzymatic amplification from mRNA by polymerase chain reaction showed that the NMB gene was expressed in all SCLC and NSCLC cell lines examined. In contrast, the GRP gene was expressed in four of six classic SCLC cell lines but not in variant SCLC or NSCLC cell lines. Immunoreactive NMB was detected by radioimmunoassay in the majority of classic SCLC, in one of three variant SCLC and in one of three NSCLC cell lines, and secreted NMB was detected in medium conditioned by a SCLC and a NSCLC cell line. The present study also demonstrated the presence of immunoreactive GRP in the absence of detectable GRP gene expression. The antiserum used in the GRP radioimmunoassay failed to cross-react with NMB but showed some cross-reactivity with amphibian phyllolitorin raising the possibility that certain SCLC cell lines may produce a phyllolitorin-like peptide.

 

Characterization of ligand-binding and processing by gastrin releasing peptide receptors in small cell and non-small cell lung cancer cell lines.
C. Cardona, J.G. Reeve & N.M. Bleehen
British Journal of Cancer 1990, 62; 474-548
Abstract
Bombesin (BN) and its mammalian homologue gastrin releasing peptide (GRP) have been shown to stimulate the growth of small cell lung cancer (SCLC) cell lines in vitro However, no obvious correlation was observed between the in vitro response to BN/GRP and the presence of specific BN/GRP receptors. Furthermore, the processing events that occur after BN/GRP binding have not been investigated in lung tumour cell lines. To gain further insight into the mechanisms involved in the mitogenic action of BN/GRP, the expression of GRP receptors and the kinetics of GRP binding and internalization have been studied in a panel of 10 SCLC and 3 non-SCLC (NSCLC) cell lines. For the detection of GRP receptors 106 cells were incubated with 0.5 nM ’25IGRP for 30 minutes at 37°C in the presence or absence of 1 pM cold GRP. Cells were pelleted, washed and specific binding determined. In contrast to previous studies, specific GRP binding sites were detected consistently on all SCLC and NSCLC cell lines examined although GRP binding varied between lines (0.06-2.01 fmol 10-6 cells). For all cell lines, binding of ’25IGRP increased rapidly with time, peaked after 15-60 minutes depending on cell line, and subsequently decreased. Extraction of surface-bound ligand at low pH indicated that the iodinated peptide was internalized within minutes in both SCLC and NSCLC cells. Pre-incubation of cells with GRP markedly reduced the subsequent binding of ’25IGRP to SCLC cells but not to NSCLC cells. These results indicate that GRP receptors are present on both SCLC and NSCLC cells, that in both cell types GRP is internalized and degraded, but that in contrast to NSCLC cells, surface receptors for GRP on SCLC cells are down-regulated. Hence regulation of the proliferative response to GRP stimulation may differ in these cells

 

Stimulation of B-chronic lymphocytic leukemia populations by recombinant interleukin-4 and other defined growth-promoting agents.
Ghaderi AA, Richardson P, Cardona C, Millsum MJ, Ling N, Gillis S, Ledbetter J, Gordon J.
Leukemia. 1988 Mar;2(3):165-70.
Abstract
Monoclonal populations from 10 cases of phenotypically well-characterized B-chronic lymphocytic leukemia (B-CLL) and from a single case of hairy cell leukemia were assessed for their ability to respond by mitogenic stimulation to a number of agents described as growth-promoting for normal B cells. These included the recombinant factors interleukin-1 (IL1), IL2, IL4, IL5, and gamma-interferon, partially purified B cell growth factor (BCGF), B cell stimulatory factor 2 (BSF2), and a CDw40 antibody to the Bp50 antigen. With only few exceptions, no factor or combination of factors stimulated B-CLL populations directly to DNA synthesis. By marked contrast, the hairy cells were responsive to IL4, BCGF, and the CDw40 antibody. B-CLL cells could become responsive with the inclusion of the phorbol ester TPA (12-O-tetradecanoylphorbol-13-acetate) as co-stimulant such that half of the populations were now activated by IL4, particularly when BCGF was also present. Populations refractory to IL4 were, nonetheless, still responsive to BCGF. In only three cases was a significant effect seen with IL2. gamma-interferon could be either inhibitory or stimulatory and, in a few cases, modulated specifically the effects of IL4. In contrast to normal B cell activations, neither the CDw40 antibody nor a calcium ionophore synergized with TPA for stimulating the majority of B-CLL populations. BSF2 was stimulatory in the two cases examined while both IL1 and IL5 were ineffective where studied. No simple correlation was observed between the patterns of responsiveness and the expression of a panel of CD markers assayed on cells both freshly isolated and after TPA stimulation. The data demonstrate a functional heterogeneity not disclosed by simple phenotypic analysis and also indicate the range of activities which can impinge on the growth regulation of monoclonal B cell populations.