Memoria Simposios Científicos (2002 - 2012)

Transcripción

Simposio Científico Fundación Lilly
La Fundación Lilly contempla entre sus objetivos favorecer y canalizar iniciativas de
colaboración social y sanitaria en España. Son sus fines generales contribuir al desarrollo y
mejora de la salud de los ciudadanos, llevando a cabo programas y actividades de
investigación, formación, divulgación, prevención, consultoría, asistencia técnica y
desarrollo de proyectos, en el ámbito de la Sanidad.
En el ámbito de nuestras actividades de apoyo a la investigación y divulgación del
conocimiento, la fundación organiza semestralmente un Simposio Científico.
Bajo el epígrafe de Simposio Científico de la Fundación Lilly se promueven reuniones
científicas de alta calidad sobre temas biomédicos de interés y actualidad. El objetivo es
ofrecer a profesionales de los ámbitos científicos y sanitarios la actualización de sus
conocimientos, en los temas elegidos, con el concurso de personas relevantes del mundo
académico e investigador.
A través de su Consejo Científico Asesor, la Fundación Lilly determinó seis áreas de
conocimiento a abordar: química médica; enfermedades metabólicas; cáncer;
enfermedades cardiovasculares; neurociencia; y enfermedades infecciosas. La realización
semestral hace que se vuelva al tema concreto cada tercer año. Hasta la fecha han sido
organizados 21 Simposios Científicos.
Distinguished Career Award
A comienzos del año 2008 y como parte de las acciones de
promoción de la I+D en Biomedicina en España, el Consejo
Científico de la Fundación Lilly, propuso la creación del Lilly
Distinguished Career Award, que se entrega coincidiendo con
cada Simposio Científico de la Fundación Lilly. El premiado lo es
a propuesta de la/las Sociedad Científica correspondientes al
área de conocimiento de cada evento.
Está distinción, pretende reconocer la trayectoria investigadora de científicos españoles –
trabajando en España o fuera de ella- que, a lo largo de su carrera, han enriquecido su
área de conocimiento, contribuyendo a aumentar su nivel científico, y a generar
vocaciones entre sus colaboradores.
Memoria Simposio Científico Fundación Lilly (2002 - 2012)
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Distinguished Career Award “Chemistry” 2008
Prof. José Elguero Bertolini
17 de abril de 2008
Distinguished Career Award “Endocrinology & Nutrition” 2008
Prof. Manuel Serrano Ríos
14 de noviembre de 2008
Distinguished Career Award “Cancer” 2009
Prof. Mariano Barbacid Montalbán
27 de Abril de 2009
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Distinguished Career Award “Cardiovascular Diseases” 2009
Prof. Alfonso Castro Beiras
Distinguished Career Award “Neuroscience/Psychiatry” 2010
Profesora Carmen Leal Cercós
11 de marzo de 2010
Distinguished Career Award “Microbiology” 2010
Profesor Fernando Baquero Mochales
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Distinguished Career Award “Chemistry” 2011
Profesor José Barluenga Mur
14 de abril de 2011
Distinguished Career Award “Endocrinología & Nutrición. Obesidad” 2011
Profesor Fernando Baquero Mochales
Distinguished Career Award “Cancer” 2012
Profesor Ciril Rozman
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er
El I Simposio Científico de la Fundación Lilly, organizado por la Fundación Lilly y la división de Discovery Chemistry
Research & Technologies de Lilly, está dedicado al repaso y actualización de los "Avances Recientes en Síntesis
Orgánica". En este sentido, el Comité Organizador ha elegido un plantel de expertos de primera fila mundial, que
estamos convencidos concitará el interés y la participación de los asistentes y satisfará las expectativas de todos.
La reunión la pensamos como un homenaje a los científicos españoles, y para hacerlo, hemos querido utilizar el mejor
método que conocemos: reunirlos alrededor de la Ciencia misma, contada por algunas de las figuras más importantes
dentro del área de conocimiento de la Química Orgánica, punto de partida de las nuevas moléculas que habrán de
aliviar las enfermedades en el futuro.
Es posible que en la antigüedad se pudiera hablar únicamente de la medicina como “la ciencia de la salud”. Sin embargo
en la actualidad, una empresa tan ingente como el descubrimiento de los mecanismos más íntimos del funcionamiento
de la vida y los métodos para reparar sus alteraciones, solo se puede abordar desde un enfoque multidisciplinar. Hoy no
es posible concebir un proyecto biomédico de envergadura sin la participación de médicos, farmacólogos, químicos,
biólogos, toxicólogos, analistas, especialistas en elucidación estructural y en purificación de sustancias químicas,
expertos en computación, estadísticos o especialistas en tecnologías de la información, entre otros muchos.
Sin embargo, son los investigadores que ponen el conocimiento básico de la ciencia, y las tecnologías que facilitan su
desarrollo y aplicación, la parte fundamental de este engranaje. Sin ellos, el edificio de la Ciencia no se sostendría.
Con esta idea hemos confeccionado el programa de este I Simposio Científico de la Fundación Lilly, dedicado a los
Avances Recientes en Química Orgánica, que esperamos contribuya a reforzar el entusiasmo por la excitante época de
explosión en el conocimiento científico y los nuevos avances tecnológicos, que nos ha tocado vivir.
El Comité Organizador, mayo de 2002
1º Simposio Científico Fundación Lilly
“AVANCES RECIENTES EN SÍNTESIS ORGÁNICA”
 Presidido por Jesús Ezquerra, José A. Gutiérrez Fuentes
 Celebrado en el Palacio Duque de Pastrana de Madrid.
 Participación: 300 asistentes
 Fecha: 28 y 29 de mayo de 2002.
Programa del Simposio en la página web (www.fundacionlilly.com)
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Programa
28-29 de mayo de 2002
Palacio Duque de Pastrana, Paseo de la Habana 208, 28036 Madrid
Martes, 28 de mayo de 2002
16:00 - 16:30
Apertura
Moderador de la sesión: Iván Collado
16:30 - 17:30
The Application of Molecular Rearrangements to the Concise Synthesis of Natural Products
Prof. Leo A. Paquette
Universidad Estatal de Ohio
As synthetic methodology advances, pressure increases to arrive at targeted structures in highly stereoselective
fashion, with good atom economy, and in as few steps as possible. These goals can be realized in notable fashion
by the proper deployment of molecular rearrangements. In this lecture, attention will be given to specific
examples where the superb scaffolding power of the so-called 'squarate ester cascade' and anionic sigmatropy are
shown to be instrumental in delivering complex natural products in a highly efficient manner.
17:30 - 18:00
Café
18:00 - 19:00
New Cyclization Reactions Catalyzed by Transition Metals
Prof. Antonio M. Echavarren Pablos
Universidad Autónoma de Madrid
Electrophilic metal complexes promote the anti attack of alkenes onto the (?2-alkyne)metal complexes to give
cyclopropyl metal carbenes as intermediates, which react with alcohols or water to give cyclized derivatives. A
similar type of reaction was found in the intramolecular reaction of allylsilanes and allylstannanes with alkynes.
Furans can also be used instead of alkenes to finally afford substituted phenol derivatives. The scope, mechanistic
aspects, and new developments will be presented.
Miércoles, 29 de mayo de 2002
Moderador de la sesión: José Alfredo Martín
9:00 - 10:00
10:00 - 11:00
Asymmetric Synthesis Made Simple: Discovery of Novel Reactivity Leading to Practical Processes
Prof. Erick M. Carreira
Instituto Tecnológico de Zurich
A novel concept for the development of asymmetric catalytic C-C bond forming reactions will be presented
involving the in situ activation of terminal acetylenes under mild conditions. In this regard, we have recently
documented the addition of terminal acetylenes to nitrones and aldehydes under mild conditions utilizing catalytic
Zn(II) and amine base. In the coupling reactions of acetylenes, the use of the inexpensive commercially available
amino alcohol ligands was observed to furnish optically active propargylic alcohols and hydroxylamines in
excellent enantioselectiviy and yields. We have also recently documented the use of [Ir(COD)Cl]2 as a catalyst for
the addition reaction of Me3SiCCH to simple N-benzyl and N-allyl imines. Both the Zn(II) and Ir(I) chemistry are
notable for their convenience, as these can be run in the absence of solvent without rigorous exclusion of
moisture or air.
Fischer Carbene Complexes: Flexible and Versatile Substrates in Organic Synthesis
Prof. José Barluenga
Universidad de Oviedo
In this lecture, several transformations using group 6 Fischer carbene complexes, of interest in selective organic
synthesis, will be presented. In this sense, pentacarbonyl(alkoxy)carbene-chromium and -tungsten complexes
have proven as highly useful intermediates in the synthesis of acyclic and cyclic molecules. The marked p-acceptor
behavior of metal pentacarbonyl moiety makes these complexes appropriate substrates for reactions with
different nucleophiles.Processes involving pentacarbonyl complexes bearing alkenylcarbene and alkynylcarbene
ligands will be reported. Asymmetric transformations using either optically active complexes or nonracemic, chiral
substrates, will receive special attention
Moderadora de la sesión: Carmen Somoza
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11:30 - 12:30
Recent Studies in the Synthesis of Natural Products and the Development of New Synthetic Methodology
Prof. William R. Roush
Universidad de Michigan
Recent studies in the total synthesis of structurally complex, biologically active natural products will be presented.
Studies on the development of new synthetic methodology involving the aldol reaction or the reactions of
carbonyl compounds with novel allylmetal reagents (of the allylboron or allylsilane families) also will be presented.
12:30 - 13:30
The Chemistry - Medicine Continuum: New Therapeutic Leads, New Reactions, New Drug Delivery Systems
Prof. Paul A. Wender
Universidad de Stanford
Studies in our laboratory focus on the synthesis and investigation of molecules of structural, biological, and
medicinal significance. Representative of this program are natural products such as taxol, phorbol, and bryostatin.
This lecture will focus on the interplay of chemistry, biology and medicine leading to the design of a fascinating
cancer therapeutic lead moving toward clinical trials (background: Proc. Natl. Acad. Sci. USA 1998, 95, 6624; J. Am.
Chem. Soc. 1998, 120, 4534) and a series of fundamentally new transition metal catalyzed reactions (e.g., J. Am.
Chem. Soc. 1998, 120, 10976; 2000, 122, 7815; 2002, 124, in press). A further product of this multidisciplinary
program is the identification of compounds that solubilize and facilitate cellular and tissue uptake of a variety of
drug and probe cargoes, findings that have led to a new biotech company, CellGate Inc. (recent references
include: Nature Medicine 2000, 6, 1253-1257; Proc. Natl. Acad. Sci. USA , 2000, 97, 13003).
13:30 - 15:00
Comida
Moderador de la sesión: Carlos Jaramillo
15:00 - 16:00
Total Synthesis of Indole Alkaloids. Biomimetic and Non-biomimetic Approaches
Prof. Joan Bosch
Universidad de Barcelona
The following syntheses will be discussed: a) a straightforward synthesis of indole alkaloids of the ervitsineervatamine group, via a dihydropyridinium cation that can be envisaged as a synthetic equivalent of the key
intermediate in the biosynthesis of these alkaloids; b) an enantioselective synthesis of pentacyclic Strychnos
indole alkaloids involving a biomimetic transannular cyclization as the key step; and c) a general entry to Strychnos
alkaloids via a common advanced intermediate, which has culminated in the synthesis of (-)-Strychnine.
16:00 - 17:00
Organic Synthesis in a Changing World
Prof. Steven Ley
Universidad de Cambridge
With the ever increasing demand for new compounds, synthetic chemists have been expected to accelerate
greatly their rate of production of new chemical entities. The preparation of biologically active and many other
functional materials from small, commercially available building blocks inevitably involves more that one synthetic
step. For most modern drugs and other complex molecules, it is not uncommon to require at least 10 steps and
sometimes many more. In order to address these goals we believe a much better practical solution for the
preparation of large chemical libraries rather than use solid phase organic synthesis would be to use solidsupported reagents in a designed sequential and multi-step fashion. In combination with advances in the use of
scavenging agents and catch and release techniques even greater opportunities for organic synthesis become
apparent. This lecture will present results from our laboratories towards this goal.
Moderadora de la sesión: Concepción Pedregal
17:30 - 18:30
New Applications of Zirconocenes in Synthetic Methodology
Prof. Peter Wipf
Universidad de Pittsburgh
The hydrozirconation of alkenes and alkynes is one of the most versatile and direct pathways for the formation of
organometallic intermediates organic synthesis. Due to the steric shielding of the C-Zr bond by the
cyclopentadienyl ligands, however, many applications of organozirconocenes been limited to oxidative cleavage
with halogens. In addition to chloride abstractions with silver(I) salts and subsequent cascade processes initiated
by formally cationic zirconocenes, transmetalation of the C-Zr bond to other metal salts is an effective way to
utilize the potential of the organozirconocene intermediate for carbon-carbon bond formation. We have
previously developed protocol for Zr–>Zn which allows in situ addition to aldehydes, and, in the presence of chiral
ligand, the enantioselective preparation of allylic alcohols. In this lecture, I will report recent developments of our
methodology studies with zirconocenes as well as applications of catalytic asymmetric carboaluminations and
water-accelerated Claisen rearrangements.
“Hace ahora ochenta años, dos médicos, el Dr. Eskil Kylin, de Goteburgo, y el Dr. Gregorio Marañón, de
Madrid, publicaron por separado, casi simultáneamente, y en la misma revista (Zentralblatt für Innere
Medizin), un trabajo de título muy parecido: Hipertensión y diabetes mellitus. Ambos trabajos llamaban la
atención hacia un determinado tipo de enfermos que, además de tener la tensión arterial elevada, también
presentaban, o bien intolerancia a la glucosa o diabetes del adulto. Los autores sugerían en sus respectivas
publicaciones un origen común en el desarrollo de la enfermedad, ya que se trataba de manifestaciones
coincidentes. De esta manera, Kylin y Marañón avanzaban una hipótesis básica sobre la patogenia del
síndrome metabólico, cuyo cuadro clínico fue descrito casi 70 años más tarde. Efectivamente, parece que la
hiperinsulinemia, relacionada con una resistencia a esta hormona, se encuentra estrechamente vinculada a
la hipertensión arterial, aún cuando la fisiopatología de esta relación permanece algo enigmática. Más aun,
queda por explicar si el desarrollo de todas las manifestaciones clínicas del síndrome metabólico obedece a
un mecanismo común.
Este encuentro científico pretende contribuir a actualizar y clarificar los conocimientos referentes a la
fisiopatología del síndrome metabólico, para lo que esperamos contar con una rica discusión basada en los
datos experimentales y la experiencia personal de nuestros ponentes.
Todos los participantes en el simposio, ponentes y audiencia, proceden de distintas disciplinas o
especialidades médicas, y han sido invitados a participar por su experiencia y relación profesional con el
síndrome metabólico, ya sea desde la vertiente clínica o la investigadora. De todos esperamos una activa y
fructífera participación.”
El Comité Organizador, noviembre de 2002
“EL SÍNDROME METABÓLICO EN SU 80 ANIVERSARIO”. En honor a los
Profesores Gregorio Marañón y Eskyl Kylin
 Presidido por Antonio García García y Antonio Ruiz-Torres.
 Celebrado en el Auditorio del Hospital de La Princesa, Madrid.
 Participación: 200 asistentes.
 Fecha: 22 y 23 de noviembre de 2002.
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En honor a los Profesores Gregorio Marañón y Eskyl Kylin
Presidentes: A. García García y A. Ruiz-Torres
MADRID, 22-23 Noviembre, 2002
Hospital de La Princesa (Calle Diego de León, 62, Madrid)
Viernes, 22 de noviembre
9:10 – 9:40
Gregorio Marañón, a relevant personality in the history of Spanish Medicine
Prof. A. Fernández de Molina
Reconocido como figura cumbre en el horizonte intelectual del siglo XX en España, Gregorio
Marañón realizó una contribución notable a la medicina y las humanidades. Después de breves
comentarios sobre el currículo marañoniano se analizarán las cuatro etapas de su vida (1909-19221936-1943-1960) para descubrir la continuidad y congruencia en su vida y obra, a pesar de los
periodos históricos tan difíciles que le tocó vivir. Finalmente, se exponen los principales capítulos
de la Obra médica de Marañón.
Discusión
9:40 – 10:10
Eskyl Kylin, a short summary of his research on hypertension and the Metabolic syndrome in the
1920’s
Dr. P. Nilsson
The Swedish physician Eskil Kylin (1889-1975) published already in 1923 a review on the Metabolic
syndrome, including aspects of hypertension, hyperglycaemia and hyperuricaemia. In other
scientific works he described aspects of essential hypertension in association with calcium
metabolism and influence of adrenaline on haemodynamics and glucose metabolism. Therefore it
is of interest to further study his ways of thinking and doing experimental medicine, in order to
increase the knowledge about the medical history of the Metabolic syndrome based on insulin
resistance.
Discusión
10:15 – 10:45
10:45 – 11:15
Café
Insulin resistance and cardiovascular disease – the Uppsala studies
Prof. H. Lithell
In Uppsala, Sweden, a cohort study started in 1970 with a health survey of 2300 men. They have
then been invited every 10 years. Annual checks of the official cause of death registry have been
made. During almost 30 years follow-up insulin resistance was an independent and strong risk
factor for coronary heart disease. Diet, physical exercise and anti-hypertensive treatment are
environmental factors that influence insulin resistance.
Discusión
The Metabolic syndrome in Spain
11:30 – 12:00
Prof. M. Serrano Ríos
The term Metabolic syndrome refer to a collection of "clusters" of metabolic (DM/IGT, visceral
obesity, dislypidemia, hyperuricemia), nonmetabolic (high blood pressure, altered
coagulation/fibrinolysis), and proinflammatory markers (CRP, IL-6), conferring high cardiovascular
risk/morbidity/mortality; insulin resistance being often a link between those "clusters". The
etiology is multifactorial, polygenes/environmental factors (diet, physical activity, smoking, alcohol
intake). Several criteria are used for definition. In Spain, R. Gabriel, M. Serrano Rios, et al, using
OMS/EGIR criteria have reported an overall prevalence similar to other European countries
(15.5/19%). A crossectional population based study of MS (ATPIII/criteria) conducted in the
Castilian province of Segovia is reported and commented.
Discusión
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12:15 – 12:45
Genetics of the Metabolic syndrome
Prof .L. Groop
Several single nucleotide polymorphisms (SNPs) or combinations of them (haplotypes) have been
identified in type 2 diabetic individuals in genes encoding for the beta-2 and beta-3-adrenerigc
receptors, calpain 10, skeletal muscle glycogen synthase (GYS1), PPARγ, sulfonylurea receptor (SUR)
etc. For other genes like adiponectin or the uncoupling proteins, the association has been with
obesity or the Metabolic syndrome rather than with type 2 diabetes. However, each of these genes
contributes only a small proportion to the individual and population risk of type 2 diabetes and this
contribution seems to differ among different parts of the world. The population attributable risk
for the Pro12Ala polymorphism in the PPARγ gene is about 20 %, whereas for the calpain 10
haplotype is 14% in Mexican Americans, but only 4% in Europeans. More importantly, the risk is
further influenced by environmental factors like diet (PPARγ ) or excercise (GYS1).
Discusión
13:30 – 15:15
15:30 – 16:00
Almuerzo
Insulin Resistance and the Metabolic syndrome: lessons from transgenic animal models
Prof. Fátima Bosch
La diabetes tipo 2 está asociada a alteraciones patofisiológicas complejas y es difícil determinar
que defectos son primarios y cuales consecuencias secundarias de los cambios metabólicos. En
nuestro laboratorio estamos estudiando, en animales transgénicos que sobrexpresen enzimas
claves en el control de las vías metabólicas (GK y PEPCK), el papel del tejido adiposo, músculo
esquelético y células ß en el desarrollo de resistencia a la insulina y a la obesidad. Los resultados
obtenidos en estos modelos serán discutidos.
Discusión
16:15 – 16:45
Magnesium and calcium homeostasis in insulin resistance and the Metabolic syndrome
Dr. A.Hänni
During the hyperinsulinemic euglycemic clamp test the changes in circulating mineral status are
correlated to alterations in blood pressure. A more pronounced increase in the circulating ionized
calcium and magnesium concentrations was related to a greater blood pressure decline. Both body
mass index and insulin-mediated glucose disposal, were correlated to the changes in serum
aldosterone concentration during the hyperinsulinemia.
Discusión
17:00 – 17:30
17:30 – 18:00
Café
Tissue-specific role of IRS-s in the insulin resistance syndrome
Prof. M. Benito
Type-2 diabetes is a polygenic disease based on a defect in the peripheral insulin action and also a
pancreatic insulin secretion deficiency. Insulin resistance in peripheral tissues such as skeletal
muscle, adipose tissues and liver is the most important feature of pre-diabetic states. To study the
insulin action and inaction, several monogenic and polygenic mouse models carrying nulls
mutations on insulin resistant genes such as insulin receptor, IRSs, Glut-4, Glucokinase have been
developed. In addition, using such models we obtained to new cellular lines to study the role of
IRSs in the tissue-specificity of insulin action and resistance.
Discusión
18:15 - 18:45
Non metabolic effects of insulin on the vascular tissue
Dr. D. Vicent
Vascular complications are the major cause of mortality and morbidity in diabetes mellitus and
other insulin resistant conditions. Experiments in cell cultured models have revealed that insulin
effects in vascular tissues can be both, protective and deleterious. The generation of an endothelial
cell-specific insulin receptor knockout mouse has revealed that, even though insulin is not a central
regulator of vascular function, it plays an important role in vascular biology.
Discusión
Sábado 23 de noviembre
9:30 – 10:00
Neuroendocrine alterations in the Metabolic syndrome
Dr. P. Nilson
Neuroendocrine aspects of the Metabolic syndrome are becoming increasingly important in the
understanding of its pathophysiology. Recent studies have indicated that disturbances in cortisol
metabolism, gonadal sex hormone regulation, and sympathetic nervous activity have all been
associated with the Metabolic syndrome. Even fetal programming could possibly influence stress
susceptibility and neuroendocrine function. This new understanding could hopefully give new
opportunities for treatment possibilities in the future
Discusión
10:15 – 10:45
Endothelial dysfunction in diabetes and Metabolic syndrome
Dr. L. Rodríguez Mañas
En el diabético, la disfunción endotelial se asocia a la enfermedad y, más concretamente, a
mecanismos ligados a la hiperglucemia, entre los que cabe destacar los debidos a la glicación no
enzimática de proteínas. Aunque tradicionalmente se ha prestado mayor atención a los productos
terminales (AGEs), los productos de Amadori, incluyendo la glicohemoglobina, parecen
desempeñar también un papel relevante.
Discusión
11:00 – 11:30
11:30 –12:00
Café
Metabolic syndrome and coronary heart disease
Prof. P. González Santos
Independientemente de la gran capacidad aterogénica de la DM tipo 2, en los últimos años se ha
comprobado que la resistencia a la insulina y la hiperinsulinemia, en ausencia de diabetes, tienen
un papel destacado en la patogenia de la enfermedad coronaria, habiéndose encontrado una
correlación positiva en algunos estudios prospectivos. El riesgo está condicionado por la asociación
con HTA, obesidad central, alteraciones trombogénicas y, sobre todo, hipertrigliceridemia y
alteraciones lipoprotéicas.
Discusión
12:15 – 12:45
Lipid treatment of the Metabolic syndrome, example from the Scandinavian Simvastatin Survival
Study
Prof. A. G. Olsson
Plasma lipid abnormalities of the Metabolic syndrome include high plasma triglyceride, low HDL
cholesterol concentrations and increased levels of small dense LDL. The 4S investigated if
treatment of patients with coronary heart disease and increased cholesterol concentration with
20-40 mg of simvastatin could prolong life. Results showed that patients with elevated LDL-C, low
HDL-C, and elevated triglycerides were more likely than patients with isolated LDL-C elevation to
have other characteristics of the Metabolic syndrome, had increased risk for CHD events on
placebo, and received greater benefit with the statin therapy.
Discusión
13:00 -13:30
Dr. R. Carraro: Comentarios y conclusiones
Prof. A. García García: Despedida
Dr. J. A. Gutiérrez Fuentes: Agradecimientos y despedida
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Es el cáncer la segunda causa de muerte en el mundo occidental. No debe sorprender por ello que la mayoría de las compañías
farmacéuticas hayan incluido a la oncología entre sus objetivos de descubrimiento de nuevos fármacos. A pesar de las mejoras en el
manejo y tratamiento de esta enfermedad, los avances en oncología no progresan todos a la misma velocidad. Por un lado es muy
halagador ver como los avances en el conocimiento básico se suceden a gran velocidad; solo hace 20 años que el primer gen
provocador de cáncer fue descrito en tumores humanos, y hoy tenemos ya identificados más de 200 genes implicados al menos en un
tipo de cáncer. Más aun. Estos genes están siendo caracterizados funcionalmente, y hoy hablamos ya de rutas oncogénicas mas que de
oncogenes o supresores tumorales individuales. El desciframiento del genoma humano ha allanado el camino hacia el conocimiento en
profundidad de la naturaleza molecular del cáncer, y más importante aún, hacia nuevas formas de diseñar aproximaciones
experimentales a los tumores humanos que queremos investigar. La posibilidad de trabajar con miles de genes a la vez está abriendo
nuevas aproximaciones a la patología molecular que nos permiten ya considerar a un tumor como una entidad molecular única, mas
que como una caja negra en la que considerar cada gen por separado.
El ritmo de progreso de la oncología clínica es mucho más lento. Un prestigioso oncólogo expresaba su justificada frustración en una
reciente reunión sobre cáncer señalando que los mayores logros en el tratamiento del cáncer durante la última década habían
sobrevenido de los avances en las técnicas quirúrgicas y el tratamiento de los efectos adversos de los tratamientos adyuvantes que de
nuestra capacidad para matar las células tumorales. De hecho hemos llegado a una encrucijada en el tratamiento del cáncer. La
quimioterapia citotóxica no parece nos vaya a aportar un enriquecimiento del arsenal terapéutico en el futuro próximo. Ello hace que
los intereses se vuelvan hacia la búsqueda de fármacos de nueva generación diseñados para impactar directamente aquellos genes
directamente implicados con el desarrollo del cáncer. El reto no es fácil. Mientras se anuncian “drogas maravillosas” como Glivec la
tozuda realidad es que otras no han satisfecho las expectativas.
Resulta muy posible que el desarrollo de nuevos fármacos, especialmente los requeridos para el tratamiento de tumores sólidos,
requerirá aproximaciones multidisciplinares que incluyan la patología molecular y la información farmacogenómica para apoyar la
situación del oncólogo clínico.
Ahora, como nunca, existe una urgente necesidad de aunar los esfuerzos de los científicos básicos y los oncólogos clínicos; su
conocimiento y su experiencia. Partiendo de este convencimiento, la Fundación Lilly ha organizado este Simposio Científico, como parte
de su objetivo de promover el intercambio de conocimientos entre las comunidades preclínica y clínica, no solo en cáncer, sino en todas
las áreas de la investigación biomédica en las que quedan retos por afrontar. Estamos seguros de que este Tercer Simposio sobre
Cáncer: Dianas Moleculares para Nuevos Tratamientos, tendrá el mismo éxito que los que le han antecedido.
Mariano Barbacid, abril de 2003
“CÁNCER: DIANAS MOLECULARES PARA NUEVOS TRATAMIENTOS”
 Presidido por Mariano Barbacid.
 Celebrado en el Auditorio San Carlos del Hospital Clínico de Madrid.
 Fecha: 25 y 26 de abril de 2003.
17
PROGRAMA
Presidente: Mariano Barbacid
Pabellón San Carlos, Hospital Clínico
Madrid, 25 y 26 de abril, 2003
Viernes 25
08:30 – 09:00
Recogida de Acreditaciones
Acto de apertura y bienvenida


09:00

APERTURA
09:20
Excmo. Sr. D. José I. Echániz Salgado, Consejero de Sanidad Comunidad Autónoma de Madrid
Dr. Mariano Barbacid, Director Centro Nacional de Investigaciones Oncológicas
José A. Gutiérrez Fuentes. Director Fundación Lilly
CONFERENCIA DE APERTURA / KEYNOTE ADDRESS
Moderador: Mariano Barbacid
Julio Celis
Scientific Director, Institute of Cancer Biology, Danish Cancer Society. Copenhaguen, Din
Proteómica y genómica funcional en la investigación translacional del cáncer: hacia una
aproximación integrada / Proteomics and Functional Genomics in Translational Cancer
Research:Towards an Integrated Approach
Today, the application of novel technologies from proteomics and functional genomics to the
study of cancer is slowly shifting to the analysis of clinically relevant samples such as fresh
biopsy specimens and fluids, as the ultimate aim of translational research is to bring basic
discoveries closer to the bedside. The implementation of discovery driven translational
research, however, will not only require co-ordination of basic research activities, facilities and
infrastructures, but also the creation of an integrated and multidisciplinary environment with
the participation of a dedicated team of clinicians, oncologists, pathologists, epidemiologists as
well as industrial partners. Issues related to sample collection, handling and storage, number of
patients, availability of normal controls, tissue banks, quality of the clinical information, followup studies are critical and must be carefully considered.
Here I will describe our experience in establishing translational research programs in bladder
and breast cancer
SESION 1
TRANSDUCCIÓN DE SEÑALES / SIGNALLING I
Moderador: Rafael Rosell. Hospital Ramón Trias i Pujol. Barcelona, Es
10:00
Julian Downward
ICRF. London, UK
Supervivencia celular: función de PI 3-kinasa y Raf / Signalling cell survival by PI 3-kinase and
Raf
Two signalling pathways are activated by most growth factors and the Ras oncogenes:
phosphatidylinositol 3-kinase and Raf/MAP kinase. These pathways both impact on the ability
of cells to resist programmed cell death in a number of ways. We have used a variety of
approaches to characterise these mechanisms in an attempt to understand how tumour cells
acquire resistance to apoptotic stimuli.
10:30
10:45 – 11:15
11:15
Discusión
Café
Manuel Hidalgo
The Johns Hopkins Univ. Baltimore, EEUU
Inhibidores mTOR en el tratamiento del cáncer / mTOR inhibitors in cancer treatment
The mammalian target of rapamycin (mTOR) is a serine-threonine kinase involved in the PI3K/AKt signaling
pathway that participates in the regulation of multiple biological phenomena such as control of transcription
and translation of certain proteins. Rapamycin and analog compounds are natural occurring inhibitor of mTOR
that have demonstrated antitumor effects in preclinical cancer models. Currently, two rapamacyn analogs,
CCI-779 and Rad001 are in clinical development. CCI-779 demonstrated significant antitumor affects in phase I
and Phase II studies and is currently in Phase III trials. The development of mTOR inhibitors present some
unique difficulties given the lack of significant toxicities encountered in Phase I studies, the observation of
clinical responses at doses different from the maximum tolerated dose, and the preclinical data suggesting that
these drugs are more effective in tumors with hyperactivated PI3/Akt signaling pathway. Ongoing efforts
include the integration of pharmacodiagnostic tests to define the population of patients more likely to respond
to these drugs and the use of pharmacodynamic endpoints to guide dose and schedule selections.
11:45
Discusión
19
SESION 2
12:00
TRANSDUCCIÓN DE SEÑALES / SIGNALLING II
Moderador: Juan A Velasco. Lilly Research Labs. Alcobendas, Madrid, Es
Mariano Barbacid
Modelos animales en cáncer / Animal models for cancer
Today we know of a number of genes that are mutated in human cancer. It is accepted that
these genes might be valid targets for the development of specific anti-tumour drugs. The
success of STI-571 in CML attests to this assumption. Yet, treatment of solid tumours that, unlike
leukaemias, may harbour several mutations, has not been equally successful. Our laboratory is
using gene-targeted mice to test whether ablation of certain targets will affect tumour
development. These results should provide valuable information to validate targets before
embarking in costly drug discovery programmes. Specifically, I will present our current results
using conditional strains of knock out mice for farnesyl transferase and Cdk2.
12:30
Discusión
12:45
Said Sebti
H. Lee Moffitt Cancer Center and Research Inst. USF, Florida, EEUU
Inhibidores de la Farnesiltransferasa: desde la farmacología molecular a los ensayos clínicos
basados en hipótesis / FT inhibitors: from molecular pharmacology to hypothesis-driven clinical
trials
This talk will focus on discussing important issues relating to the mechanism by which
farnesyltransferase inhibitors (FTIs) inhibit tumor growth and induce apoptosis. Potential
biochemical targets as well as signaling pathway targets for FTIs will be discussed. The talk will
conclude with how some of the laboratory bench findings are being translated in the patient bed
side. Results from 2 hypothesis-driven clinical trials we have conducted will be discussed.
13:15
Discusión
14:00
Almuerzo
RUTAS ONCOGÉNICAS / ONCOGENIC PATHWAYS I
SESION 3
16:00
Moderador:
Carlos Martínez CNB. Madrid, Es
Jonathan Yingling
Eli Lilly. Indianapolis, EEUU
La ruta de transducción de señales TGFβcomo diana terapéutica en cáncer / Targeting the TGF
Signal Transduction Pathway for Cancer Therapy
The transforming growth factor beta pathway plays diverse roles in tumor biology. Early in the
evolution of many tumors, the TGF growth inhibitory pathway is disrupted leading to increased
cell proliferation. Paradoxically, enhanced expression of TGF contributes to creation of a
microenvironment conducive to tumor growth by promoting angiogenesis and epithelial-tomesenchymal transition, remodeling of the extracellular matrix, and immunosuppression.
Identification of potent, selective, orally bioavailable TGF receptor inhibitors has led to an
effective anti-tumor therapy in preclinical models.
16:30
Discusión
16:45
Moshe Oren
Dean, Weizmann Institute of Science, Faculty of Biology. Rehovot, Isr
Pérdida de función y mutaciones de p53 en cáncer / Wild type p53 loss of function and mutant
p53 gain of function in cancer
Half of all human cancers carry p53 gene mutations. Mutant p53 can downregulate CD95
expression and protect against CD95-induced apoptosis. In tumors that retain a wild type p53
gene, p53 function is nevertheless defective. In some cases, the defect is due to expression of
dominant negative p63. Elimination of DNp63 triggers p53-mediated apoptosis.
17:15
17:30 – 18:00
Discusión
Café
RUTAS ONCOGÉNICAS / ONCOGENIC PATHWAYS Ii
SESION 4
18:00
Moderador:
Eugenio Santos CIC. Salamanca, Es
Richard Gaynor
LRL. Indianapolis, EEUU
Regulación de la via NF-kB / Regulation of the NF-B Pathway
This talk will be focused on the role of the IB kinases on regulating the NF-B pathway in response to
cytokine activation. Novel functions of these kinases in NF-B activation will be discussed.
18:30
Discusión
18:45
Hans Clevers
Centre for Biomedical Genetics, UMC. Utrecht, Hol
El complejo beta-catenina/TCF determina un fenotipo progenitor oculto en las células cancerosas
colorectales / The beta-catenin/TCF complex imposes a crypt progenitor phenotype on colorectal
cancer cells
Mutations in the Wnt pathway components APC, beta-catenin and conductin all induce sustained
complex formation of the co-activator beta-catenin with TCF transcription factors. The resulting
transactivation of TCF target genes is believed to represent the primary transforming event in
colorectal cancer (CRC). Yet, the consequence of the presence of mutationally activated betacatenin/TCF in fully transformed CRC cells is unknown. We have constructed CRC cell lines carrying
inducible dominant-negative TCF constructs. Inhibition of beta-catenin/TCF resulted in a rapid G1
arrest. DNA array analysis revealed the downregulation of a small set of transcripts. These genes were
expressed in polyps, but also, physiologically, in the crypt progenitor compartments of the colon. By
contrast, we observed the induction of multiple marker genes of intestinal differentiation upon
inhibing beta-catenin/TCF in CRC cells. We provide evidence that p21 is responsible for this
phenomenon. We conclude that beta-catenin/TCF inhibits differentiation and imposes a crypt
progenitor phenotype on CRC cells. Moreover, inhibition of beta-catenin/TCF activity restores the
differentiation program, despite the presence of multiple other mutations in CRC.
19:15
Discusión
Sábado 26
GENÓMICA DEL CÁNCER / CANCER GENOMICS
SESION 5
09:15
09:45
10:00
10:30
Moderador:
Eduardo Díaz-Rubio. Hospital Clínico. Madrid, Es
Marc J van de Vijver
Dept. of Pathology, Netherlands Cancer Institute, NL
Microarrays y cáncer de mama / Microarrays and Breast cancer
We have used gene expression profiling to identify a gene expression profile that is associated with
a high risk to develop distant metastases within five years in lymph node negative patients
younger than 55 years. This “prognosis signature” consists of 70 genes; this includes genes that
play a role in cell cycle control, invasion and angiogenesis. More recently, we have found that this
“prognosis signature” is also associated with poor outcome in lymph node positive patients. An
important use of the “prognosis signature” is to guide systemic adjuvant treatment of patients
with operable breast cancer.
Discusión
Miguel Angel Piris
Head, Molecular Pathologie Programme, CNIO. Madrid, Es
Elaboración de predictores de resultados en linfomas / Building outcome predictors in lymphoma
Molecular massive techniques have been now applied to the analysis of different types of
lymphoid malignancies. Essentially the results are showing that human tumours carry on a huge
constellation of molecular alterations in genes and pathways regulating cell cycle, apoptosis, signal
transduction and other critical pathways.
The identification of this myriad of alterations in the level of expression of multiple genes allows to
integrate this information into predictive systems, this permitting to stratify patients into different
levels of risk to treatment-failure, with an unprecedented accuracy. A further step in this pathway
has been the identification of molecular signatures which allow to differentiate conditions such as
malignant and inflammatory diseases. Molecular signatures permit also to deconstruct the
pathogenesis of common tumours, such as it’s being doing for the elucidation of the role of key
genes in the pathogenesis of the most common lymphoma types.
Discusión
21
10:45 – 11:15
Café
NUEVOS TRATAMIENTOS / NOVEL THERAPIES
SESION 6
11:15
Moderador:
Hernán Cortés. Hospital 12 de Octubre. Madrid, Es
Axel Ullrich
Director, Dept. of Molecular Biology, Max Planck Institute of Biochemistry. Martinsried, Al
Desde el gen al tratamiento del cáncer / From gene to cancer therapy
Gene technology methods have opened new ways towardsthe elucidation of aberrant processes in
cancer cells that are causally connected to the development and progression of tumors. The first
gene-based cancer therapeutic confirming the validity of this paradigm is “HERCEPTIN”
Which targets the oncoprotein HER2/neu in breat cancer. Other examples including antiangiogenic strategies will be presented.
11:45
12:00
12:30
12:45
13:25
DESPEDIDA Y CIERRE
Discusión
José Baselga
Chairman, Medical Oncology Serv. Hosp. Vall d´Hebron. Barcelona, Es
Inhibidores de tirosin quinasa / Tyrosine kinase inhibitors
The epidermal growth factor receptor (EGF receptor) is a tyrosine kinase receptor of the ErbB
family that is abnormally activated in many epithelial tumors. Receptor activation leads to
recruitment and phosphorylation of several downstream intracellular substrates, leading to
mitogenic signaling and other tumor-promoting cellular activities. In human tumors, receptor
ovexpression correlates with a more agressive clinical course. Monoclonal antibodies directed at
the ligand-binding extracellular domain and low molecular weight (MW) inhibitors of the
receptor’s tyrosine kinase are currently in advanced stages of clinical development. These agents
prevent ligand-induced receptor activation and downstream signaling, which results in cell cycle
arrest, promotion of apoptosis, and inhibition of angiogenesis. In patients, single agent activity has
been observed in colon carcinoma, non-small-cell-lung cancer, head and neck cancer, and ovarian
carcinoma.
Discusión
Robert Pinedo
Head, Free University of Amsterdam. Amsterdam, Hol
Ensayos clínicos en cáncer en la próxima década / Cancer Clinical Trials in the next decade
Cancer therapy is changing dramatically. While most cytotoxic therapies were far from being
tumor specific, we are experiencing an increasing number of targeted treatments entering the
clinic. This will require a change of mind of clinical oncologists. In the next 10 years clinical
protocols will require a ‘translational section’ based on the type of targeted treatment under
study. Such targeted therapies differ widely, including specific types of anti-angiogenic treatments,
proteosome inhibitors, monoclonal antibodies to specific receptors/antigens and specific
immunotherapeutic approaches. Patients will need to be stratified based on biologic parameters
of the tumor, which can be assessed through genomics and proteonomic approaches. Treatment
results will be assessed through surrogate markers, including new imaging procedures.
Discusión
Mariano Barbacid & José A. Gutiérrez Fuentes
PROMOTORES
CNIO & Fundación Lilly
COMITÉ CIENTÍFICO Y ORGANIZADOR
Mariano Barbacid
Hernán Cortés
José A. Gutiérrez Fuentes
Mariano Barbacid
José Baselga
Johannes L Bos
Julio Celis
Hans Clevers
Juan Carlos Gómez
Jesús Ezquerra
Juan Angel Velasco
CONFERENCIANTES y MODERADORES
Hernán Cortés
Manuel Hidalgo
Eduardo Díaz-Rubio
Carlos Martínez
Javier Dorta
Moshe Oren
Julian Downward
Robert Pinedo
Richard Gaynor
Miguel A Piris
PATROCINIO
Fundación Lilly
LUGAR
Pabellón San Carlos. Hospital Clínico San
Carlos. MADRID
Eugenio Santos
Juan A Velasco
Marc J van de Vijver
Alex Ullrich
Jonathan Yingling
La enfermedad coronaria es una de las principales causas de muerte y de consumo de recursos sanitarios en los países
desarrollados. En España, aunque su incidencia sea inferior a la de otros países europeos, también representa un
importante problema sanitario, ya que, siguiendo la tendencia occidental, también es la primera causa de muerte en
hombres, y en algunas comunidades incluso en mujeres.
El estudio DRECE ha puesto de manifiesto, que el perfil lipídico español no es significativamente distinto al de otras
comunidades occidentales, a excepción de una concentración de colesterol de HDL (cHDL) algo más elevada, pero que no
representa en sí misma un hecho diferencial sobre otras poblaciones como la inglesa, en que la morbi-mortalidad
coronaria se estima considerablemente superior a la española.
No obstante, las diferencias en el impacto de la enfermedad coronaria en España siguen sin tener una explicación clara.
Algunos asumen la existencia de un efecto protector en nuestro país (genes, hábitos de vida, dieta española,...), otros,
consideran que simplemente estamos ante una fase de latencia relacionada con nuestra historia reciente, y otros, por
fin, dudan incluso de que esta diferencia sea real.
En cualquier caso, un hecho que sí parece cierto es que mientras en otras comunidades occidentales el impacto de la
enfermedad coronaria se está reduciendo, en España la morbilidad coronaria ha aumentado en los últimos años, y la
mortalidad por enfermedad isquémica (mortalidad proporcional), en el mejor de los casos, podemos considerar que se
mantiene estable.
¿Cuáles son las razones para que esto esté sucediendo? ¿Se están deteriorando nuestros hábitos de vida y en especial
nuestra forma de alimentarnos? ¿Qué nuevos conocimientos tenemos sobre los mecanismos de la enfermedad, y
consecuentemente cuáles son los avances en nuestra capacidad de aproximación, diagnóstico, prevención y tratamiento
de la aterosclerosis?
A estos interrogantes, y a otros de índole práctica en los Seminarios, pretendemos obtener respuestas en este Simposio.
El Comité Organizador, noviembre de 2003
“ALIMENTACIÓN LÍPIDOS Y ATEROSCLEROSIS”
 Presidido por Salvador Moncada y José A. Gutiérrez-Fuentes.
 Celebrado en el EUROFORUM Infantes de San Lorenzo de El Escorial de Madrid.
23
Chairman: José Antonio Gutiérrez & Salvador Moncada
Euroforum Infantes, El Escorial
Madrid, november 21 & 22, 2003
Viernes / Friday 21
08:30 – 08:50
08:50
MESA / SESSION 1
09:00
Recogida de Acreditaciones / Registration
Opening and welcome addresses:
Autoridades
Why this symposium.
ALIMENTACIÓN Y ATEROSCLEROSIS
Moderador / Chairperson: Luis Masana
Estilo de vida y aterosclerosis. Los estudios de Uppsala. / Life Style and Atherosclerosis. The Uppsala
Studies.
Hans Lithell
Professor (emer.) of Geriatrics. Uppsala University, Uppsala, Sweden
Fifty year old men (n=2.322) were investigated in 1970-73. All participants have been invited again every tenth
year. Cause of death and hospital care registries have been followed. Risk factors for cardiovascular disease
were investigated. Insulin resistance was important but was in its turn dependent on both exercise and food
patterns.
09:40
Dieta: alimentos y riesgo cardiovascular / Whole foods and cardiovascular risk
Emilio Ros
Head, Lipid Clinic, Nutrition & Dietetics Service, Hospital Clínico, University of Barcelona, Barcelona, Spain.
Modern nutrition has evolved from advice against consuming some foods solely to recommendations to
include other foods for beneficial health effects. In the last decade, the results of long-term prospective
studies have shown that consumption of whole foods like fish, nuts, whole cereals, legumes, alcoholic
beverages, and tea is associated with protection from atherosclerosis and its clinical manifestations. Feeding
trials that have investigated the effects of these foods on surrogate markers of atherosclerosis, such as blood
lipids, insulin resistance, oxidized lipids, or endothelial dysfunction have generally found measurable benefits.
However, clinical trial evidence of effects on cardiovascular morbidity or mortality is scarce.
10:20
Muerte súbita y consumo de aceite de pescado / Sudden death and fish oil consumption
Eliseo Guallar
Assistant Professor. Department of Epidemiology and Welch Center for Prevention, Epidemiology, and Clinical
Research. Johns Hopkins Medical Institutions. Baltimore, MD, USA
El consumo de pescado es parte de las recomendaciones para una dieta cardiosaludable. El consumo de
pescado proporciona ácidos grasos poli-insaturados n-3 de cadena muy larga (aceites de pescado) Aunque
inicialmente se pensaba que el principal efecto de estos aceites era reducir la agregabilidad plaquetaria,
modelos experimentales, estudios epidemiológicos y ensayos clínicos indican que los aceites de pescado
pueden prevenir las arritmias ventriculares y la muerte súbita.
11:00
Patrones dietéticos y enfermedad coronaria / Dietary patterns and coronary heart disease
Frank B Hu
Associate Professor of Nutrition and Epidemiology. Harvard School of Public Health, Boston, USA
Numerous studies have examined individual nutrients or foods in relation to risk of coronary heart disease
(CHD). Few studies, however, have examined the role of overall dietary patterns in Relation to CHD. Using the
data from the Nurses' Health Study and Health Professionals' Follow-up Study, we have shown that major
dietary patterns derived from factor analysis are significant predictors of CHD in both men and women. These
patterns are also significantly related to biomarkers of CHD, such as CRP, IL-6, ICAM-1, VCAM-1, and E-selectin.
These data underscore the importance of overall dietary patterns in prevention of CHD.
25
11:30 – 12:00
12:00 – 13:00
MESA / SESSION 2
14:30
Café / Coffee
SEMINARIOS (*)
ÓXIDO NÍTRICO Y ATEROSCLEROSIS
Moderador / Chairperson: Miguel Pocoví
Modelos Animales / Animal models
Fatima Bosch
Dept. Biochemistry and Molecular Biology School of Veterinary Medicine and Gene Therapy.Universidad
Autómoma de Barcelona. Spain
To determine the role of obesity in the development of type 2 diabetes, we overexpressed PEPCK, a regulatory
enzyme of glyceroneogenesis in adipose tissue. These animals developed obesity but did not become insulin
resistant. However, they develop diabetes when fed a high fat diet. To counteract insulin resistance and
obesity, expression of genes involved in the control of glucose uptake, such as glucokinase in skeletal muscle,
has been examined in high fat fed transgenic mice. These models will be discussed.
15:10
Mecanismos de transducción de señales de NO en el endotelio vascular / Vascular endothelium NO signal
transduction mechanisms
Santiago Lamas
Investigador Científico del CSIC, Consejo Superior de Investigaciones Científicas. Madrid, Spain.
Implications of nitric oxide on the regulation of endothelial cell migration and degradation of extracellular
matrix will be disscused. As the core of this presentation, data in a model of wound healing describing the
effects of NO on collagenase-3 activation will be shown.
15:50
Disfunción endotelial: papel de la interleukina 6 en el remodelado y activación de la placa vascular /
Endothelial dysfunction: role of interleukin 6 for vascular remodelling and plaque activation
Helmut Drexler
Director Departament of Cardiology and Angiology. Medizinische Hochschule Hannover, Hannover, Germany
Endothelial dysfunction plays an important role in cardiovascular disease and is attributed to several
mechanisms including oxidative stress, inflammation and activation of the renin-angiotensin system. This
presentation outlines mechanisms and functional consequences of endothelial dysfunction and inflammation
for vascular disease and arteriosclerosis
16:30
Terapias NO en aterosclerosis / NO therapies in atherosclerosis
Arnold Herman
Professor of Pharmacology, University of Antwerp, Belgium
Rupture-prone atherosclerotic plaques contain numerous macrophage-derived foam cells and few smooth
muscle sells(SMC).Decreasing the ratio between macrophages and SMC might favor plaque
stabilization.Macrophages expressing inducible nitric oxide synthase become hypersensitive to killing by
exogenous NO donors.Treatment of cholesterol-fed rabbits with the NO donor molsidomine increased the
subendothelial macrophage-free layer consisting mainly of SMC,and normalized both superoxide production
and superoxide dismutase expression.These findings demonstrate that molsidomine decreases signs of
oxidative stress and increases features of stable atherosclerotic plaques.
17:00 – 17:30
Conferencia
18:30 – 19:30
Café / Coffee
Moderador / Chairperson:
Reto ante la aterosclerosis / The challenge ahead in atherosclerosis
J Anthony Ware
Vice President, Cardiovascular Research and Clinical Investigation, Eli Lilly and Company, USA
Although many advances have occurred in the treatment of atherosclerosis, the morbidity and mortality from
this disease are increasing. New therapies are needed to reduce the risk of atherosclerosis to reduce the size
of atherosclerotic plaques, and to prevent ischemia in those with severe disease.
17:30 – 18:30
SEMINARIOS (*)
Sábado / Saturday 22
MESA / SESSION 3
09:00
DIAGNÓSTICO DEL RIESGO CARDIOVASCULAR
Moderador / Chairperson: Fernando Fabiani
Lipoproteínas residuales. Medición y significado clínico / Residual lipoproteins. Quantification and clinical
significance
José Mª Ordovás
Professor Nutrition and Genetics at Tufts University. Boston, USA
Postprandial lipid metabolism has received considerable attention since it was shown that postprandial
triglyceride-rich lipoproteins are involved in the development of atherosclerosis. The interindividual
differences in postprandial lipid metabolism are dramatic and they are in part due to genetic factors that could
be used in the near future for better prediction of cardiovascular risk.
09:40
Dímero D y enfermedad coronaria / D-dimer and coronary heart disease
Ann Rumley
Departament of Medicine, Haemostasis, Thrombosis & Vascular Medicine Section, University of Glasgow,
Glasgow, UK
Fibrin D-dimer, a marker of cross-linked fibrin turnover, is now routinely used in the diagnosis of clinically
suspected venous thromboembolism. Over the past 10 years, we have evaluated the predictive value of
plasma D-dimer (within the population range) for CHD and stroke. A meta-analysis of prospective CHD studies
showed a significant, independent association with risk. 3 recent studies have also shown that D-dimer is an
independent predictor of stroke.
10:20
Proteína C Reactiva como marcador de riesgo coronario / C reactive protein as a coronary risk marker
Juan A. Gómez Gerique
Director. Servicio de Bioquímica Clínica, FJD-UNILABS, Madrid, España
La proteína C reactiva un clásico marcador de inflamación aguda, está emergiendo como un potente predictor
de accidentes cardiovasculares. La elevación moderada de la concentración de PCR parece indicar un estado
de inflamación de bajo grado, característico del proceso de arteriosclerosis. Por otra parte, las estatinas,
fármacos que son capaces de disminuir significativamente la incidencia de accidentes cardiovasculares,
también son capaces de hacer disminuir las concentraciones de PCR. En esta ponencia revisaremos la
información disponible por el momento.
11:00
Efectos antiaterógenos del HDL / Antiatherogenic effects of HDL
Arnold von Eckardstein
Director and Professor of Clinical Chemistry, Institute of Clinical Chemistry, University Hospital of Zurich,
Zurich, Switzerland
Low HDL cholesterol is an important independent cardiovascular risk factor, which contributes to the
estimation of global CHD risk by scores and algorithms. HDL and its protein and lipid components exert a
broad scope of potentially antiatherogenic effects, which make them an interesting target for anti-atherogenic
therapy.
11:30 – 12:00
Café / Coffee
12:00 – 13:00 : SEMINARIOS (*)
Conferencia de Clausura Moderador / Chairperson: José A. Gutiérrez Fuentes
13:00 – 14:00
El óxido nítrico:¿amigo o enemigo? / Nitric oxide: friend or foe?
Salvador Moncada
Director of The Wolfson Institute for Biomedical Research, University College London, UK
Nitric oxide is a physiological activator of guanylate cyclase. In addition, it inhibits cytochrome c oxidase in a
reversible manner and in competition with oxygen. It is likely that this effect has a significance physiological
relevance and also has pathophysio-logical implications.
27
SEMINARIOS
SEMINARIO 1
Alimentación y ECV: aproximación práctica en prevención primaria y secundaria / Nutrition and CVD:
practical approach in primary and secondary prevention
Miguel A. Rubio
Unidad de Nutrición y Dietética. Hospital Clínico San Carlos, Madrid, España.
Descripción de la relación de los ácidos grasos con el metabolismo lipídico.
Descripción de alimentos con diferente riqueza en ácidos grasos cardioprotectores y antioxidantes.
Diseño genérico de una dieta cardioprotectora. Normas alimentarias para la prevención primaria y
secundaria.
Ejercicios prácticos.
SEMINARIO 2
Sindrome Metabólico y ECV: abordaje práctico / Metabolic syndrome and CVD: practical approach
Pedro González Santos
Head of Department of Internal Medicine. University Hospital. University of Malaga. Spain
Obesity and insulin resistance are often associated with hyperinsulinemia, glucose intolerance, hypertension,
dyslipidemia and premature atherosclerosis. This cluster of abnormalities, known as the metabolic syndrome,
has been assessed and incorporated into the guidelines of the NCEP- Adult Panel III.
We will discusses the effect of genetic and environmental factors, the link of visceral adiposity and insulin
resistance to vascular disease, and the data on the pathophysiology and treatment of metabolic syndrome.
SEMINARIO 3
Guías Clínicas y valoración del riesgo cardiovascular en el anciano / Guidelines and cardiovascular risk
evaluation in the elderly
Leocadio Rodríguez Mañas* y Juan A. Gómez Gerique
*Geriatra. Hospital Universitario de Getafe, Madrid, España
El papel que cada uno de los factores clásicos y emergentes de riesgo cardiovascular ejercen en el
desencadenamiento de enfermedades cardiovasculares y la potenciación de sus respectivos efectos cuando se
agrupan en un mismo individuo, han llevado a las autoridades sanitarias y grupos científicos de referencia a
recomendar la valoración global del riesgo cardiovascular, en función del cual se determinan las actitudes
diagnósticas y terapéuticas.
No obstante, los métodos hoy vigentes ofrecen algunas debilidades que se comentaran.
SEMINARIO 4
Información al paciente y cumplimiento terapéutico / Information to patients and therapeutical
accomplishment
Agustín Gómez de la Cámara
Head. Clinical Epidemiology Research Unit. 12 de Octubre Hospital, Madrid, Spain
The degree of hypercholesterolemia control among treated patients is poor. There is no enough data
explaining this situation. Several causes could be involved, mainly related to physicians attitude and patient
compliance. Information exchange may improve this reality.
Fundación
Lilly
PROMOTORES Y PATROCINIO
CONFERENCIANTES – SPEAKERS
Fatima Bosch (Sp)
Helmut Drexler (Ger)
Arnold von Eckardstein (Ger)
Fernando Fabiani (Sp)
Agustín Gómez de la Cámara (Sp)
Juan A. Gómez Gerique (Sp)
Pedro Gónzalez Santos (Sp)
Eliseo Guallar (USA)
Arnold Herman (B)
Frank B Hu (USA)
Santiago Lamas (Sp)
Hans Lithell (Sw)
Luis Masana (Sp)
Salvador Moncada (UK)
José Mª Ordovás (USA)
Miguel Pocoví (Sp)
Leocadio Rodríguez Mañas (Sp)
Emilio Ros (Sp)
Miguel A Rubio (Sp)
Ann Rumley (UK)
J Anthony Ware (USA)
INFORMACIÓN GENERAL Y SECRETARIA
La acreditación supondrá la asistencia a todas las sesiones plenarias y, como mínimo, a tres seminarios
Las conferencias tendrán una duración de 30 minutos y se verán seguidas por un coloquio de 10 minutos, estando abiertas al público en
general
Los seminarios se impartirán tres veces cada uno
lomitándose el número de
Al inscribirse, los asistentes harán una opción previa sobre los seminarios a los que desean asistir, lomi
participantes en cada uno de ellos un máximo de 70 (se respetará rigurosamente el orden de inscripción)
Fundación Lilly: Calle Velázquez 94, 6º Izq. 28006 Madrid
Tel: 91 781 50 70-71 / 629 86 14 16 Fax: 917815079 E-mail: [email protected] / www.fundacionlilly.com
Tel
Más del 20% del gasto sanitario en los países desarrollados se dedica a las enfermedades del sistema nervioso y es muy
posible que esta proporción aumente en el futuro. Según los cálculos de la Organización Mundial de la Salud sobre la
carga que suponen las enfermedades medida en DALY’s, el 9% corresponde a las enfermedades mentales, el 1,7% a las
enfermedades cerebrovasculares, y el 34% a problemas del comportamiento. En total, puede decirse que alrededor del
45% de la carga de las enfermedades corresponden al comportamiento o al órgano que lo regula. Entre las 10
enfermedades con mayor carga, 5 son trastornos mentales. No cabe pues duda que las enfermedades del sistema
nervioso son un reto sanitario de primera magnitud.
La investigación en el ámbito de la neurociencia tiene ante sí la gran tarea de conseguir aumentar los conocimientos
necesarios para hacer frente a estas enfermedades. Al mismo tiempo, la neurociencia tiene otro reto, al menos tan
importante como aquel, que es el de conocer el funcionamiento del sistema nervioso, en todo lo relacionado con nuestra
actividad psíquica y con lo que nos caracteriza como seres humanos conscientes, tanto a nivel individual como al nivel de
especie.
La neurociencia como tal nació hace algo más de 30 años cuando investigadores de campos muy diversos decidieron
cambiar sus disciplinas originarias e integrarse en esta nueva. Desde entonces, el camino recorrido es extraordinario y
esta integración en una nueva ciencia está siendo enormemente productiva. Queremos subrayar el concepto unitario de
neurociencia, y no el frecuentemente utilizado de neurociencias. En ella, la combinación de perspectivas clínicas y
básicas de aquellos que estudian el cerebro en el amplio marco de la diversidad humana, y los que se interesan por sus
alteraciones, ha demostrado ser un camino fructífero y apasionante. Hasta hace poco nadie pensaba que era posible
hacer convivir perspectivas evolucionistas, que estudian cómo el cerebro se ha ido adaptando y adaptando a responder
a retos, exigencias y cambios del medio ambiente, con otras que proceden de la psicología cognitiva, que estudian las
estrategias que utiliza para conocer y actuar. Por vez primera, el ser humano está cerca de alcanzar lo que durante
siglos han sido los sueños de filósofos y pensadores y, en el fondo, la inquietud de cualquier ser humano.
Este simposio pretende atraer estas perspectivas diferentes manteniendo el hilo conductor de la respuesta que la
investigación del sistema nervioso puede dar ante el reto de enfermedades muy discapacitantes, algunas de las cuales
han sido la causa de temores y estigmas muy extendidos a lo largo de los siglos, y que han tenido su origen en la
ignorancia y los prejuicios.
Comité Científico Organizador, abril de 2004
“NEXO ENTRE CEREBRO Y MENTE. RETOS DE LA INVESTIGACIÓN EN
NEUROCIENCIAS"
 Presidido por Juan José López-Ibor y Francisco Mora.
29
PROGRAMA
Chairmen: Juan José López-Ibor & Francisco Mora
Pabellón San Carlos, Hospital Clínico
Madrid, April 23 & 24, 2004
Viernes / Friday 23
08:30 – 08:50
08:50
Keynote Address
09:00
 Why this symposium
Moderador/Chairperson: Juan José López-Ibor
Servicio de Psiquiatría. Hospital Clínico San Carlos, Madrid, Es
Arvid Carlsson
Department of Pharmacology. University of Göteborg, Sw
The Dopamine System: Still an important target for Drug Discovery - El Sistema Dopamínico: aun una diana
importante para el descubrimiento de fármacos
Following the proposal by Carlsson and Lindqvist in 1963 that major neuroleptics act by blocking dopamine (and
noradrenaline) receptors, the dopamine system has been a target in attempts to discover novel antipsychotics with
improved balance between efficacy and side effects. The present paper will deal with the most recent group of agents
acting on this target, i.e. the dopamine system stabilizers; they seem to offer significant advantages compared to
current antipsychotics.
SESION 1
09:40
Parkinson's disease
Moderador/Chairperson: Juan Carlos Gómez, Departamento Médico. Lilly S.A., Madrid, Es
Peter Jenner
Neurodegenerative Diseases Research Centre. GKT School of Biomedical Sciences, King’s College, London, UK
Molecular mechanisms in Parkinson’s disease - Mecanismos moleculares de la enfermedad de Parkinson
Neuronal cell death in Parkinson’s disease may be associated with a failure of proteaolysis linked to alterations in the
function of the ubiquitin-proteasome system. Inhibition of proteasomal function leads to dopaminergic cell death both
in vitro and in vivo. Inflammatory changes also occur in the substantia nigra in PD as a result of reactive gliosis. Glial
cell activation using LPS leads to destruction of dopaminergic neurones suggesting that inflammation may contribute to
disease progression.
10:10
José López Barneo
Departamento de Fisiología. Hospital Universitario Virgen del Rocío, Sevilla, Es
Dopamine and GDNF-producing cells in the carotid body: their use for autotransplantation in Parkinson’s disease –
Células productoras de dopamina y GDNF en el cuerpo carotídeo: su utilización para autotransplante en la
enfermedad de Parkinson
Several dopamine-producing cells have been used for the last few years in transplantation studies designed to treat
Parkinson's disease, both in human and in animal models of Parkinson's disease. We have developed a technique based
in the intrastriatal autotransplantation of cells of the carotid body that secrete dopamine and glial cell line-derived
neurotrophic factor (GDNF). We will present the status of our current research. We will also discuss the advantages,
limitations and future perspectives of this new methodology for treatment of Parkinson's disease.
10:40
11:10
Café
José Obeso
Unidad de Trastornos del Movimiento y Ganglios Basales. Univ. de Navarra, Pamplona, Es
Pathophysiology of the basal ganglia: therapeutic consequences for Parkinson’s disease – Patofisiología de los
ganglios basales: consecuencias terapéuticas para la enfermedad de Parkinson
The severity of dopamine depletion and the associated pathophysiologic abnormalities in the basal ganglia circuits
determine the severity of parkinsonian signs. Cell replacement therapy has spurred considerable enthusiasm, most
recently for the use of embryonic stem cells. However, Parkinson’s disease is a multi-systems degeneration; many
symptoms fail to respond to current treatment and will likely be resistant even to the most “successful” dopamine
cellular replacement therapy.
31
11:40
Eduardo Tolosa
Servicio de Neurología. Hospital Clínic, Barcelona, Es.
Emerging strategies in the treatment of Parkinson disease – Nuevas estrategias en el tratamiento de la enfermedad
de Parkinson
In recent years new treatments have become available that have greatly improved both motor and non-motor
complication of Parkinson disease. These include new atypical antipsychotics and the anticholinesterase inhibitors and
stimulants such as modafinil. Newer treatments are furthermore emerging which are likely to be effective in both the
symptomatic and neuroprotective treatment of Parkinson disease, such as some trophic factors, anti-adenosine A2
receptor drugs or those with antiglutamatergic properties. These new available treatments and the new, emerging,
strategies will be reviewed.
12:10
Discusión 1: Parkinson's disease
12:45
SEMINARIO 1
13:45
SESION 2
15:15
SEMINARIO 2
Almuerzo
Schizophrenia: a neurodegenerative disorder?
Moderador/Chairperson: Enrique Baca
Servicio de Psiquiatría. Clínica Puerta de Hierro, Madrid, Es
Robin M Murray
Department of Psychiatry. Institute of Psychiatry, King’s College, London, UK
Schizophrenia: Between development and degeneration – Esquizofrenia: entre el desarrollo y la degeneración
Although the neurodevelopmental model was the predominant model of schizophrenia throughout the 1990s’s, it is
clear that it cannot explain all characteristics of schizophrenia. The question is whether the decline that occurs in a
proportion of patients is simply a consequence of the psychological and social disruption caused by psychosis or
whether this is the result of progression of brain structural and neuropsychological abnormalities.
15:45
Tim Crow
Prince of Wales International Centre for Research into Schizophrenia and Depression. Oxford, UK
An evolutionary perspective on schizophrenia - Una perspectiva evolutiva sobre la esquizofrenia
Schizophrenic illnesses occur in all populations whit similar features. Some balancing advantage to the biological
disadvantage associated with the generic predisposition is required. This, it is suggested, is the human capacity for
language, and that the relevant genetic variation goes back to the origin of the species at some point in E. Africa 100150.000 years ago.
16:15
Maria Carlsson
Sahlgrenska Academy (Medical School), Institute of Clinical Neuroscience. Univ. of Göteborg, Sw
The role of glutamate in schizophrenia – Papel del glutamato en la esquizofrenia
Cognitive and negative symptoms of schizophrenia constitute the major therapeutic challenges in this disorder. This
presentation will discuss recent findings from our rodent hypoglutamatergic models for cognitive and negative
symptoms of schizophrenia. The effects of traditional neuroleptics, a newer generation antipsychotics, as well as those
of so called dopamine stabilizers will be presented.
16:45
Gary D Tollefson
Lilly Research Laboratories. Indianapolis, USA
Neuroprotection and cognitive enhancement. The future of the treatment of schizophrenia – Neuroprotección y
mejora cognitiva. Futuro del tratamiento de la esquizofrenia
While undoubtedly schizophrenia has a neurodevelopmental aspect, both studies of associated clinical and structural
brain pathomorphology suggest a progressive course. The loss of cortical gray volume and ventricular enlargement
represents a new treatment target. Data suggesting a neuroplasticity benefit with the atypical olanzapine will be
shared.
17:15
Discusión 2: Schizophrenia: a neurodegenerative disorder?
17:45
Café / Coffee
18:15
SEMINARIO 1
SEMINARIO 3
SESION 3
09:00
Alzheimer's disease
Moderador/Chairperson: Justo García de Yébenes, Servicio de Neurología. Fundación Jiménez Díaz, Madrid, Es
Ezio Giacobini
University Hospitals of Geneva, Department of Geriatrics. University of Geneva, Ch
Early diagnosis and treatment of Alzheimer’s disease: present and future – Diagnóstico temprano de la enfermedad de
Alzheimer: presente y futuro
Various forms of pharmacological treatment are being tested clinically in an effort to slow down or block the conversion
of Mild Cognitive Impairment to Alzheimer’s Disease. Experimental and clinical data suggest that cholinesterase
inhibitors (ChEI), in addition to symptomatic benefit, might have a delaying effect on Alzheimer’s Disease progress
(Giacobini, 2000). Other approaches being investigated include anti-inflammatories (rofecoxib), 1200 pats, 3yrs; antioxidants (vit E) + ChEI (donepezil), 769 pats, 3 yrs; nootropics (piracetam), 675 pats, 1yr; AMPA receptor agonists
(ampakine), 160 pats, 4 wk. Besides, data from the recent vaccination study (Nitsch et al, 2003; Hock et al, 2003), with
pre-aggregated A-beta-42, show that patients who generated amyloid plaque immunoreactivity over one year period,
had significantly slower rate of decline of cognitive functions and improvement in activities of daily living. These
preliminary results suggest that targeting A-beta with immunization could be of benefit to early cases of Alzheimer’s
Disease.
09:30
Jesús Ávila
Centro de Biología Molecular "Severo Ochoa". CSIC, Es
Tau proteins and tauopathies – Proteínas Tau y taupatías
The role of tau protein in pathological disorders like Alzheimer’s disease, and other pathologies, has two main
characteristics: the phosphorylation of the protein, and its aberrant polymerization.
The mechanisms for these two features will be indicated.
10:00
10:30
Café
Peter Davies
Department of Pathology. Albert Einstein College of Medicine, New York, USA
Tau pathology and tangles in Alzheimer's disease as a target for pharmacotherapy – Patología de Tau y redes como
diana farmacoterapéutica en la enfermedad de Alzheimer
Abnormalities in tau in Alzheimer’s disease include conformational changes as well as hyperphosphorylation. These
alterations are exquistively sensitive indicators of neuronal damage in this disease. There is now also evidence that tau
abnormalities are responsible for the death of neurons, and the mechanisms involved are very obvious targets for new
therapeutics.
11:00
Steven Paul
Vice President, Science and Technology. Lilly Research Laboratories. Indianapolis, USA
Alzheimer's disease: Genetic and pharmacological evidence supporting the amyloid cascade hypothesis – Evidencia
genética y farmacológica en soporte de la hipótesis de cascada de amiloide
Revolutionary advances in our understanding of the genetic and consequent cellular/biochemical etiologies of a group of
phenotypically similar neurodegenerative disorders, referred to as Alzheimer’s Disease (AD), have heralded a new era in
potential therapeutic intervention. I will review these findings, including recent data from our laboratory delineating an
important role for apoE in the process of amyloidogenesis in vivo, and present several ongoing approaches to drug
discovery made possible by this new information. Similar approaches to other neuropsychiatric disorders will
undoubtedly prove feasible once the genetic underpinnings of their etiologies are delineated.
11:30
12:00
Conferencia Clausura
13:00
Discusión 3: Alzheimer's disease
SEMINARIO 2
SEMINARIO 3
Moderador / Chairperson: Francisco Mora
Catedrático de Fisiología. Facultad de Medicina, UCM. Madrid, Es
Francesc Artigas
Profesor Investigación CSIC, IIBB. Presidente, Sociedad Española de Neurociencias
The role of prefrontal cortex in mental health and disease – Papel del cortex prefrontal en la salud y la enfermedad
mentalesl
The prefrontal cortex (PFC) is involved in many higher brain functions which are altered in severe psychiatric disorders.
PFC pyramidal neurons express the receptors for which antipsychotic drugs show high affinity. The current evidence
supporting a major role of these neurons in the pathophysiology and treatment of schizophrenia, and possibly major
depression, will be reviewed.
13:40
Despedida
Juan José López-Ibor, Francisco Mora Teruel, J. A. Gutiérrez Fuentes, J. C. Gómez Pérez
33
SEMINARIOS
Ponente: Gurutz Linazasoro
Centro de Neurología y Neurocirugía Funcional, Clínica Quirón, San Sebastián, Guipúzcoa
SEMINARIO 1
Diagnosis and treatment of Parkinson’s disease – Diagnóstico y tratamiento de la enfermedad de Parkinson
Since no biological markers of the disease are available, the diagnosis of PD is still based on clinical grounds. Clues to
establish a diagnosis will be explained as well as recent advances in complementary tests. Current management of early
and late PD will be reviewed emphasizing the role of recent therapies and the potential of emerging therapies.
Ponente: Enrique Álvarez
Jefe del Servicio de Psiquiatría del Hospital de Sant Pau de Barcelona
SEMINARIO 2
Diagnosis and treatment of Schizophrenia – Diagnóstico y tratamiento de la Esquizofrenia
La era de la Medicina Científica debe estar presente también en la Psiquiatría. Los clínicos apoyaran sus decisiones en
pruebas científicas de su utilidad. Por otra parte la era de la terapéutica de caja negra ha terminado y los Psiquiatras
emplearan fármacos de los que conocerán su intimo mecanismo de acción.
Ponente: Manuel Martínez Lage
Profesor y Consultor de Neurología, U Trastornos de Memoria, Clínica Universitaria de Navarra, Pamplona
SEMINARIO 3
Diagnosis and treatment of Alzheimer’s disease – Diagnóstico y tratamiento de la enfermedad de Alzheimer
-
Early detection of Alzheimer’s disease
Clinical, biological, and imaging markers
AchE inhibitors: donepezil and rivastigmine
Nicotinic AchER modulators: galantamine
Memantine
Treatment of behavioral and psychological symptoms
Antiamyloid therapies. Facts and hopes
Cognitive psychostimulation
Viernes 21
Sábado 22
12:45
SEM- 1
18:15
SEMI-2
SEM- 1
12:00
SEM- 3
SEM- 2
SEM- 3
Seminarios: dirigidos a la discusión y orientación de los aspectos prácticos relacionados con la prevención, el diagnóstico y el tratamiento
PROMOTORES PATROCINIO
Fundación Lilly
LUGAR DE CELEBRACIÓN DEL SIMPOSIO
Madrid
COMITÉ CIENTÍFICO (ORGANIZADOR)
Juan José López-Ibor
Francisco Mora Teruel
José Antonio Gutiérrez Fuentes
Juan Carlos Gómez Pérez
Juan José López-Ibor (Es)
Arvid Carlsson (Sw)
Eduardo Tolosa (Es)
Peter Jenner (UK)
José López Barneo (Es)
José Obeso (Es)
Juan Carlos Gómez (Es)
Enrique Baca (Es)
Robin M Murray (UK)
Tim Crow (UK)
Maria Carlsson (Sw)
Gary D Tollefson (USA)
Justo García de Yébenes (Es)
Ezio Giacobini (Ch)
Jesús Ávila (Es)
Peter Davies (USA)
Steven Paul (USA)
Francisco Mora (Es)
Francesc Artigas (Es)
Gurutz Linazasoro (Es)
Enrique Alvarez (Es)
José Manuel Martínez-Lage (Es)
INFORMACIÓN GENERAL
La acreditación supondrá la asistencia a todas las sesiones plenarias y, como mínimo, a tres seminarios
Las conferencias tendrán una duración de 30 minutos y se verán seguidas por un coloquio de 10 minutos, estando abiertas al público en general.
Los seminarios se impartirán tres veces cada uno. Al inscribirse, los asistentes harán una opción previa sobre los seminarios a los que desean asistir,
limitándose el número de participantes en cada uno de ellos un máximo de 70 (se respetará rigurosamente el orden de inscripción)
SECRETARIA
Tel: 91 781 50 70-71 / 629 86 14 16 - Fax: 917815079 - E-mail: [email protected] / www.fundacionlilly.com
En términos generales, nuestro título “Evolución de las Enfermedades Infecciosas” quiere referirse a la serie de
eventos sucesivos que caracterizan la emergencia, desarrollo, diseminación, variación o desaparición de aquellas
interacciones entre microbios y humanos que resultan en una pérdida de capacidades para el hombre. En
términos biológicos, la evolución de las enfermedades infecciosas contempla los aspectos en que colisionan, la
biología evolutiva de los microorganismos y la biología evolutiva del hombre, colisión que puede eventualmente
resolverse de forma co-evolutiva.
En los humanos, la biología evolutiva necesariamente resulta del binomio entre genes y cultura. Durante los
últimos siglos, la cultura ha provocado cambios muy rápidos en la biología del hombre (medicina, sociología,
higiene), y también en el medio ambiente (agricultura, ganadería, industria), con inevitables consecuencias en la
interacción de humanos y microorganismos.
Cualquier cambio significativo en la red de interacciones entre seres vivos debe dar lugar a nuevas interacciones –
algunas se pierden, otras emergen, otras se modifican-. Para los microbios, la adaptación a nuevas situaciones
interactivas se basa en cambios genéticos –verdadera evolución-. La adaptación de los humanos tiene también –
sobre todo tuvo- bases genéticas, pero, a la velocidad actual de cambio medioambiental, la única posibilidad
adaptativa de los humanos reside en su cultura. La imparable tendencia hacia el imperialismo humano (el hombre
dueño de la Tierra) puede dar lugar a un frágil pseudo-equilibrio que podría evolucionar hacia la aparición de
nuevas interacciones patogénicas entre humanos y microbios, esto es, a un nuevo espectro de enfermedades
infecciosas. El progreso en la cultura humana, progreso en la ciencia y en la conciencia, es la única salida.
El objetivo de este Simposio Científico es contribuir a orientar el progreso en esa dirección de equilibrio.
Comité Científico Organizador, noviembre de 2004
“EVOLUCIÓN DE LAS ENFERMEDADES INFECCIOSAS”
 Presidido por Fernando Baquero Mochales y César Nombela Cano.
 Celebrado en el EUROFORUM Infantes de San Lorenzo de El Escorial de
Madrid.
35
PROGRAMA
Chairmen: Fernando Baquero & César Nombela
Place: Euroforum Infantes, El Escorial (Madrid)
Date: November 19 & 20, 2004
Viernes / Friday 19th
08:15
08:45
 Why this symposium
Keynote Address
09:00
Moderador / Chairperson: Fernando Baquero
Bruce R Levin
Professor of Biology, Emory University, Department of Biology. Atlanta, USA
Population biology, evolution and infectious disease: an opinionated
perspective /Biología poblacional, evolución y enfermedad infecciosa: una perspectiva
obstinada
For more than two decades, investigators trained in precious, academic population and
evolutionary biology have been studying infectious diseases and their treatment and prevention.
What have they accomplished? In this talk I will review what I consider to be the major
achievements of this enterprise and consider the kinds of questions and issues that I believe
people in this area should be addressing. My talk will be unabashedly opinionated and our own
work in this area will, doubtless, be over represented.
SESION 1
09:40
The Interplay of Human and Microbial Evolutionary Biology / La interacción entre las
evoluciones humana y microbiana
Moderador / Chairperson: Antonio Rodríguez Noriega
Servicio de Microbiología Clínica, Hospital Ruber Internacional. Madrid
Jörg Hacker
Professor, Head of the Institute for Molecular Biology of Infectious Diseases
University of Würzburg. Germany
Making friends: from pathogenicity to commensalisms / Haciendo amigos: de la
patogenicidad al comensalismo
The genome of pathogenic as well as non-pathogenic microbes consists of a core region and of a
so-called flexible gene pool. Genomic islands represent parts of the flexible gene pool and they
can encode “additional factors”, which may be necessary for adaptation of non-pathogenic
microbes to certain habitats, but also for disease-related processes of pathogens. The aim of the
presentation is to describe genomic islands of pathogenic and non-pathogenic enterobacteria and
to show how the respective gene products interact with host factors in order to increase the
fitness as well as the pathogenicity of particular bacterial isolates.
10:10
Carmen Álvarez Domínguez
Investigador Facultativo, Servicio de Inmunología
Hospital Universitario Marqués de Valdecilla, Santander. Spain
From commensalism to intracellularity / Del comensalismo a la intracelularidad
Pathogens have adapted to intracellular spaces mainly to remain hidden from the host defense
mechanisms and find specialized niches that fulfilled their nutrient requirements. Actually the
regulation of this specialized trafficking known as phagocytosis is beginning to be unrevealed.
The identification of both, host regulators and microbial factors involved in the phagocytic
trafficking will discover the strategies of pathogens to survive intracellularly and evade the
immune system.
37
10:40
11:10
Café / Coffee
César Nombela
Catedrático de Microbiología y Director de la Cátedra Extraordinaria MSD de Genómica y
Proteómica . Facultad de Farmacia. Universidad Complutense de Madrid. Spain
Breaking the equilibrium: multifactorial basis for opportunistic pathogenicity of
Candida albicans / Rompiendo el equilibrio: bases multifactoriales para la
patogenicidad oportunista de Candida albicans
Candida albicans is a successful commensal in the human body that can invade multiple sites,
thus producing a wide range of infections, from superficial to deep-seated. More than 50 gene
products have been identified as required for virulence in model systems used for experimental
infection. Our approach to analyse the transition to a pathogenic state is, on one hand, to study
the activation of fundamental signalling pathways (cell integrity, high osmolarity glycerol) under
the challenging conditions that the fungus must face in the host. The response is based on a
regulated cross-talk between signalling pathways controlled by MAP kinases Mkc1 and Hog1. On
the other hand, by proteome technology we observed specific changes in protein expression
during the Candida-macrophages interaction. We have identified 36 fungal proteins whose
expression is altered by interaction with the macrophage, several of them being induced by the
oxidative products related to the phagocyte anticandidal activity.
11:40
Marc Lipsitch
Associate Professor, Epidemiology and Immunology and Infectious Diseases
Harvard School of Public Health. Boston, MA, USA
What maintains diversity and virulence in pathogens? / ¿Qué mantiene la diversidad y
virulencia en los patógenos?
Conventional wisdom has answered the twin questions of: why are surface structures of
pathogens variable (because host immunity directed against one variant creates selective
pressures favoring the others), and why do pathogens harm their hosts (as a by-product of
selection for reproduction within and transmission between hosts). While there are multiple
examples consistent with each of these stories, especially in viruses, there are also many
important microbes for which these explanations are difficult to support. Understanding the
diversifying and virulence-maintaining forces in natural populations is important for basic
population biology and for applications such as vaccine design. This talk will briefly examine
some of the examples, supportive and otherwise, for these generalizations and consider some
alternative and possibly general mechanisms for maintenance of diversity and virulence.
12:10
12:45
Discussion General Topic 1
SEMINARIO 1
13:45
SESION 2
15:15
SEMINARIO 2
Almuerzo
Changing Ecology and Evolution of Infectious Diseases / Cambiando la ecología y
evolución de las enfermedades infecciosas
Moderador / Chairperson: José María Eirós Bouza
Centro Nacional de Microbiología, Instituto de Salud Carlos III. Spain
Dieter Ebert
Professor, Zoological Institute
University of Basel. Basel, Switzerland
Host-parasite coevolution / Coevolución huésped-parásito
What evidence do we have for antagonistic coevolution by negative frequency dependent
selection? In the first part of my talk I introduce a couple of experiments aimed to test for
aspects of antagonistic coevolution between hosts and parasites. In the second part I discuss the
consequences of coevolution for the genetic structure of populations and for their evolution.
15:45
Juan Ortín
Profesor de Investigación
Centro Nacional de Biotecnología, CSIC. Madrid, Spain
From animal to human viruses: the case of respiratory pathogens / De los virus
animales a los humanos: el caso de los patógenos respiratorios
The Influenza A viruses are members of the Orthomyxoviridae family that contain as genome a
set of 8 ssRNA molecules of negative polarity. These RNAs form RNP structures that transcribe
and replicate independently in the nucleus of the infected cell. Influenza A viruses are genetically
and antigenically variable. Many subtypes can be distinguished, depending on the structure of the
surface antigens HA and NA. All viral subtypes replicate in wild avian species, without signs of
pathology, while a subset of these subtypes infect mammals, including man, and produce
disease. Normally new Influenza viruses can enter the human host by reassortment of RNPs in
individuals infected by a normal human virus and an avian virus, but recently some avian viruses
have crossed the species barrier and produced disease in man. The possibility that these viruses
may develop into a new pandemic strain has raised special concern. The possibility of crossing
the species barrier is limited for avian Influenza viruses by the lack of adaptation to replicate in
the mammalian host. Thus, the steps of adsorption to cells, membrane fusion, transcription and
replication of virus RNA and modulation of the cell antivirus response involve virus-host
interactions that are optimized for each virus-host pair. The interspecies shift needs to overcome
the barriers imposed by inexistent or inefficient interactions. Unfortunately, the large
heterogeneity of the influenza virus populations, their continuous evolution and the possibility for
the avian viruses to incorporate human-adapted RNPs by reassortment will allow the appearance
of new viruses in the human population and eventually a new pandemic. The consequences of
such pandemic for human health will depend upon the pathogenicity of the virus strain, the time
elapsed until identification of the new virus and the public health measures adopted worldwide.
16:15
David Heymann
Representative of the Director-General for Polio Eradication
World Health Organization. Geneva, Switzerland
Factors in the evolution of infectious diseases / Factores en la evolución de las
enfermedades infecciosas
The microbes that cause infectious diseases are complex, dynamic, and constantly evolving. They
reproduce rapidly, mutate frequently, and adapt with relative ease to new environments and
hosts, and they develop resistance to the drugs used to treat them. Social, economic and
environmental factors linked to a host of human activities often accelerate and amplify the
natural phenomena that modify infectious disease patterns in humans, increasing the ease at
which the microbes that cause them adapt to new environments and hosts, and the speed with
which they develop resistance to the antimicrobial agents that treat them.
16:45
Michel Tibayrenc
Director, Unit of Research Genetics and Evolution of Infectious Diseases
UMR CNRS/IRD 9926. Montpellier, France
Human genetic diversity and the evolution of infections / Diversidad genética humana
y evolución de las infecciones
Environmental factors are crucial for the transmission and severity of infectious diseases. However, for
the same socioeconomical and medical environment, we are unequal before transmissible diseases.
Resistance genes have been evidenced, for example in the case of malaria, lepra and schistosomiasis,
and family studies have detected important individual differences. However, resistances to transmissible
diseases are complex phenotypes. It is my belief that: (i) the genetic background of these complex
phenotypes is also complex, that is to say: multigenic; (ii) the target of natural selection for these
complex phenotypes is much more the population, even the ethnic group, rather than the individual
(Tibayrenc, 2004). When ethnic groups are concerned, it has been proposed that the morphological and
colorimetrical diversity of our species is the result of sexual selection (Harpending, 2002). However
natural selection by climatic parameters plays an obvious role in it. Since the transmission of infectious
diseases is strongly influenced by climatic factors, I suggest that ethnic diversity is a relevant
parameter for the study man genetic susceptibility to transmissible diseases.
In this seminar, I will expose what is known presently on the overall genetic diversity of our species and
on the genetic differences (in particular HLA polymorphism) that could explain why some population are
overall more resistant to given infectious diseases than other populations. I will speak also on the
potential interest of the “Human Diversity Genome Project” (HDGP) for the study of transmissible
diseases (Tibayrenc, 2003).
17:15
Discussion general Topic 2
17:45
18:15
Café / Coffee
SEMINARIO 1
SEMINARIO 3
39
SESION 3
09:00
Intervention Strategies and the Evolution of Infectious Diseases / Estrategias de
intervención y la evolución de las enfermedades infecciosas
Moderador / Chairperson: Jerónimo Pachón
Servicio de Enfermedades Infecciosas, Hospital Universitario Virgen del Rocio. Sevilla, Spain
Javier Garau
Head, Department Of Medicine
Hospital Mutua Terrasa, Barcelona, Spain
Antibiotics and the evolution of infectious diseases / Antibióticos y evolución de las
enfermedades infecciosas
In the past 60 years, the ecology and treatment of ID have changed greatly. As a result of
excessive demand and use of antibiotics in humans, and the deployment of antibiotics in animal
husbandry, the number of organisms demonstrating resistance has increased dramatically, and
there is now a well established pool of antibiotic resistance genes in nature. Antibiotic resistance
has become a major deterrent to effective treatment and control of many infectious diseases.
Changes in the susceptible human such as reduction of immunocompetence, in social behavior
and in the environment have also taken place. Bacteria will continue to evolve under these
pressures. The impact of such basic changes will be reviewed.
09:30
Fernando Baquero
Jefe de Servicio de Microbiología
Hospital Ramón y Cajal & Centro de Astrobiología, CSIC / INTA. Madrid, Spain
Antibiotics and emergent behaviour of bacterial pathogens / Antibióticos y
comportamiento emergente de los patógenos bacterianos
Antimicrobial agents used in chemotherapy constitute a major component of the environment of
bacteria associated with humans. Bacterial adaptation to antibiotic challenges is either based on
mutational events or on extensive combinatorial trade-off of locally available genetic sequences.
As a result of the later process, a number of these sequences are amplified by selection and
become increasingly available for future adaptive combinations. Both mutational events and local
engineering inputs facilitate in some cases, and prevent in others, the building-up of new
bacterial behaviors in particular bacterial clones. Successful clones may spread efficiently,
disseminating in novel microbial environments the genetic tools that have contributed to their
wealth.
10:00
10:30
Café / Coffee
Gail Cassell
Vice President, Scientific Affairs, Eli Lilly and Company
Lilly Corporate Center. Indianapolis, USA
Immunomodification and the Evolution of Infectious Diseases: The Challenge of
Mycobacterium tuberculosis / Modificación inmunitaria y evolución de las
enfermedades infecciosas: el reto del Mycobacterium tuberculosis
Immunodification of infectious agents no doubt contributes to the agent's ability to persist within
a host as well as cause disease. Tuberculosis is one of the oldest known and well studied
infectious diseases form with regards to host/parasite interactions. Yet one third of the world's
population is latently infected with this organism. Every 15 seconds at least one person dies of
this disease. This presentation will review what is known about immunomodulation and its
involvement from both the perspective of the host and the parasite. Lastly, the threat from
multi-drug resistant tuberculosis will be discussed as an emerging global crisis.
11:00
Sunetra Gupta
Reader in Epidemiology of Infectious Disease
Department of Zoology, University of Oxford. UK
Inmmunoselection and the evolution of pathogenicity / Inmunoselección y evolución
de la patogenicidad
I will discuss the effects of immune selection on the evolution of antigenic diversity both at the
within-host and between-host level with particular reference to Plasmodium falciparum malaria.
I will show how partially cross-protective immune responses can structure a pathogen population
in to antigenically distinct ‘strains’, and also enable the orchestration of antigenic variation as a
within-host immune evasion strategy.
11:30
12:00
SEMINARIO 2
SEMINARIO 3
Closure Address
Moderador / Chairperson: César Nombela
Julian Davies
Professor, Department of Microbiology and Immunology
University of British Columbia. Vancouver, Canada
13:00
Human–microbe interactions: the future / Interacciones humano-microbio: el futuro
In the past 25 years, cellular microbiology has provided amazing insights on human-microbe
interactions, both parasitic and commensal. The evolution of microbial diseases is a real-time
phenomenon; in 1980, E. coli 0157 was not known as a human pathogen. Future work must be
concerned with the rapidity that new pathogens can appear and whether or not this can be
predicted. What are the origins of pathogenicity genes and how are they acquired? More
importantly, what makes a pathogenicity gene?
13:40
Farewell
Fernando Baquero; César Nombela; José Antonio Gutiérrez Fuentes; Juan Carlos Gómez
SEMINARIOS
dirigidos a la discusión y orientación de los aspectos prácticos relacionados con la prevención, el diagnóstico y el
tratamiento
SEMINARIO 1
Ponente: Fernando Cháves
Adjunto, Servicio de Microbiología
Hospital Universitario Doce de Octubre, Madrid
Tuberculosis, una enfermedad en evolución. Novedades diagnósticas / Tuberculosis, an
evolving disease. Diagnosis innovations
La tuberculosis es un problema de salud pública de importancia global. Las características singulares de
Mycobacterium tuberculosis, la resistencia a los fármacos, y los nuevos fenómenos epidemiológicos que
se están sucediendo, suponen importantes retos para el control de la enfermedad. Las nuevas técnicas
de epidemiología molecular están aportando importante información en la transmisión de la tuberculosis,
patogenicidad, manejo clínico de los pacientes, y en la evaluación de los programas para el control de la
enfermedad.
SEMINARIO 2
Ponente: Rafael Cantón
Adjunto, Servicio de Microbiología, Hospital Ramón y Cajal y Profesor Asociado del Departamento
de Microbiología, Facultad de Farmacia, Universidad Complutense. Madrid
La explosión de las beta-lactamasas de espectro extendido: valoración y control /
Outburst of extended spectrum beta-lactamases. Assessment and control
Las beta-lactamasas de espectro extendido (BLEE), detectadas inicialmente al principio de la
década de los 80, se han convertido en paradigma de la dispersión de los mecanismos de
resistencia, no sólo en el ambiente hospitalario sino también en la comunidad. Las BLEE están
codificadas en unidades genéticas de transferencia horizontal y con frecuencia se asocian a otros
genes de resistencia. Los procesos de co-selección y la movilidad de los genes BLEE pueden haber
tenido un papel relevante en su diseminación. El control de la explosión de las BLEE constituye un
reto actual para la microbiología y las enfermedades infecciosas.
SEMINARIO 3
Ponente: Jordi Vila
Profesor de Microbiología, Facultad de Medicina, Universidad de Barcelona, y
Consultor del Departamento de Microbiología Clínica del Hospital Clinic, Barcelona
Human migrations and infectious diseases / Migraciones humanas y enfermedades
infecciosas
Las enfermedades infecciosas son la primera causa de muerte en el mundo. El riesgo de padecer
una de estas enfermedades se ve influenciado por diferentes factores, entre los cuales se hallan la
globalización del comercio mundial, los movimientos migratorios, y el creciente tráfico aéreo. En
este seminario, se discutirán estos factores, así como la diseminación de microorganismos
específicos, y como esta puede ser prevenida y controlada.
Viernes 19
Sábado 20
12:45
SEM- 1
18:15
SEMI-2
SEM- 1
12:00
SEM- 3
SEM- 2
SEM- 3
41
PROMOCION Y PATROCINIO: Fundación Lilly
COMITÉ CIENTÍFICO (ORGANIZADOR)
César Nombela
Juan Carlos Gómez
Fernando Baquero
José A Gutiérrez Fuentes
Euroforum Infantes. El Escorial, Madrid, Spain
Álvarez Domínguez, C (Sp)
Baquero, F (Sp)
Levin, B (US)
Cantón R (Sp)
Cassell, G (US)
Chaves, F (Sp)
Davies, J (Can)
Ebert, D (Sw)
Eiros JM (Sp)
Garau, J (Sp)
Gupta, S (UK)
Hacker, J (Al)
Heymann, D (Sw)
Lipsitch, M (US)
Nombela, C (Sp)
Ortín, J (Sp)
Pachón J (Sp)
Rodríguez Noriega, A (Sp)
Tibayrenc, M (Fr)
Vila J (Sp)




La acreditación supondrá la asistencia a todas las sesiones plenarias y a los tres seminarios
Las conferencias tendrán una duración de 30 minutos y se verán seguidas por un coloquio al finalizar las
sesiones de 30 minutos, estando abiertas al público en general
Los seminarios se impartirán dos veces cada uno
Al acreditarse, los asistentes serán asignados al turno de seminarios a los que deseen asistir, limitándose el
número de participantes en cada uno de ellos a un máximo de 70
SECRETARIA
Tel: 91 781 50 70-71 / 629 86 14 16
Fax: 917815079
E-mail: [email protected] / www.fundacionlilly.com
La invención y desarrollo de un nuevo fármaco es un proceso largo, complejo, costoso y arriesgado que tiene
pocos ejemplos similares en el mundo industrial. Históricamente, como en la actualidad, la creación de un nuevo
fármaco ha cabalgado sobre todo –aunque no solamente- sobre la onda de las nuevas metodologías de síntesis.
Los nuevos métodos de síntesis, a través de los cuales los científicos pueden crear moléculas cada vez más
complejas, se encuentran con frecuencia en la base de las nuevas y cada vez más eficaces entidades moleculares
desarrolladas. De forma adicional, la actual miniaturización y automatización de las técnicas de ensayo biológico
está produciendo un avance paralelo en la mejora de la metodología de síntesis.
El séptimo Simposio Científico de la Fundación Lilly “Nuevas Fronteras en Síntesis Orgánica” ha intentado reunir
científicos con diferentes visiones y culturas en su aproximación a la creación de nuevas moléculas. Desde el uso
de enzimas y anticuerpos como catalizadores, o de herramientas químicas para estudiar sistemas biológicos
complejos, al de nuevas tecnologías como líquidos iónicos o síntesis con microondas. Desde las nuevas
aproximaciones a la síntesis de productos naturales, o el uso de síntesis en paralelo para el desarrollo de
quimiotecas, hasta el de nuevos métodos de litiación o nuevos auxiliares quirales. Desde el uso de propiedades de
auto ensamblaje hasta el desarrollo de nuevos conceptos sobre la productividad en la investigación farmacéutica.
Hemos pretendido que en todas las conferencias haya siempre un equilibrio entre dos filosofías: una, que toma de
la naturaleza su fuente de inspiración, mientras que la otra hace uso de nuevas herramientas que la tecnología va
poniendo en nuestras manos y en nuestros laboratorios. Esperamos que esta mezcla sirva para crear una
atmósfera de inspiración entre todos los participantes en el Simposio.
“NUEVAS FRONTERAS EN SÍNTESIS ÓRGANICA"
 Presidido por Julio Álvarez-Builla, Jesús Ezquerra y Fernando Albericio.
“New Frontiers in organic Synthesis". Monográfico del 7º Simposio Científico. Diciembre 2005
-
Distribución: suscriptores de la revista Anales de la Real Sociedad Española de Química y a
los asistentes al Simposio. (3.500 ejemplares)
-
Disponible en formato pdf. en la página web de la Fundación.
43
-PROGRAMA-
Chairmen: Julio Álvarez-Builla, Fernando Albericio, Jesús Ezquerra
Place: Euroforum Infantes, El Escorial (Madrid)
Date: April 15 & 16, 2005
Viernes / Friday / 15
08:15
08:45
Bienvenida / Opening and welcome addresses
Porqué este Simposio / Why this Symposium
Session 1
09:00
Moderador/Chairperson: Jesús Ezquerra
Lilly Research Laboratories. Alcobendas, Madrid, Spain
Manfred T Reetz
Director of Department of Synthetic Organic Chemistry, Max-Planck-Institut fur Kohlenforschung. Mülheim an
der Ruhr, Germany
Evolución Dirigida de Enzimas Enantioselectivos /
Directed Evolution of Enantioselective Enzymes
Applying the methods of directed evolution, i.e. the appropriate combination of gene mutagenesis and
expression and high-throughput ee-assays, the enantioselectivity of enzymes as catalysts in organic chemistry
can be controlled. This fundamentally new approach to asymmetric catalysis is independent of any knowledge
concerning the enzyme structure, yet important mechanistic lessons can be learned from directed evolution.
10:00
Barbara Imperiali
Department of Chemistry, Massachusetts Institute of Technology. Cambridge, Massachusetts, USA
Herramientas Químicas para el Estudio de Sistemas Biológicos Complejos / Chemical Tools for the Study of
Complex Biological Systems
This presentation will discuss the development and application of new chemical probes for studying complex
biological systems. In the area of signal transduction, new strategies including the preparation of synthetic and
semi-synthetic protein probes for interrogating the specific function of proteins involved in directed cell
migration and cell cycle control have been developed. Due to the essential signaling roles played by intracellular
kinase-mediated phosphorylation in key cellular processes, the focus of these studies is on protein kinases as
strategic targets. Access to chemical probes to monitor phosphorylation events will enable to define the spatial
and temporal characteristics of protein kinases and phosphoprotein mediators in complex cellular pathways.
These probes include both environment-sensitive and chelation enhanced fluorophores for interrogating
phosphorylation-dependent protein-protein interactions and caged phosphoamino acids for examining
phosphorylation-mediated cellular functions.
11:00
11:30
Café / Coffee
Carlos F Barbas III
Professor. The Skaggs Institute for Chemical Biology, The Scripps Research Institute. California, USA
De los Anticuerpos Catalíticos a la Organocatálisis / From Catalytic Antibodies to Organocatalysis
One of the ultimate goals in organic chemistry is the catalytic asymmetric assembly of simple and readily
available precursor molecules into stereochemically complex products. As chemists, we often turn to nature for
inspiration concerning stereochemically complex, diverse, and functional molecules. Indeed, the directed
asymmetric assembly of simple achiral building blocks into stereochemically complex molecules like
carbohydrates and polyketides has long been the purview of nature’s enzymes. Our approach to this problem
began in 1997 when we embarked upon studies exploring the similarity between proline and a novel class of
aldolase antibodies we had developed earlier. Recently, these studies have allowed us to describe the first
direct organocatalytic asymmetric ketone and aldehyde additions in aldol, Michael, Mannich, and Diels-Alder
reaction manifolds. Significantly, these studies were originally designed for antibody catalysis years before. This
lecture will summarize the contributions of this laboratory to creating and converting enzymatic enamines, and
in some cases imines, into a versatile catalytic asymmetric strategy powered by small organic molecules.
45
James E Audia
Executive Director, Discovery Chemistry Research & Technologies, Lilly Research Laboratories. Indianapolis, USA
12:30
Hacia una Pharma mas Productiva / Toward a more ‘Productive’ Pharma
Jim is a native of South Carolina and obtained his Ph.D. in Organic Chemistry from the University of South
Carolina in 1986 in the laboratories of Jim Marshall. Over the course of his career, Jim’s scientific endeavors
have contributed to 8 clinical candidates for development at Lilly. He is a named inventor on more than 80
issued US Patents and has published extensively in the synthetic and medicinal chemistry of serotonergic
agonists, antagonists and uptake inhibitors, steroid 5 α-reductase inhibitors, and γ secretase inhibitors.
13:30
Almuerzo / Lunch
Moderador/Chairperson: Julio Álvarez Builla
Departamento Química Orgánica, Facultad de Farmacia, Universidad de Alcalá de Henares. Spain
Session 2
Tom Welton
Department of Chemistry, Imperial College London. London, UK
15:00
Líquidos Iónicos a Temperatura Ambiente en Síntesis y Catálisis / Room-Temperature Ionic Liquids in
Synthesis and Catalysis
In the last decade there has been an explosion of interest in the use of room-temperature ionic liquids as
solvents for synthesis and catalysis. Much of the interest has centered on their on their potential as ‘green’
solvents. This lecture goes beyond this to see how ionic liquids can be used to change synthetic and catalytic
processes. Examples will be shown of ionic liquids being used to effect the yields, rates and selectivities of
reactions.
William R Roush
Executive Director of Medicinal Chemistry, The Scripps Research Institute. Florida, USA
16:00
Nuevos Métodos Síntéticos y Aplicaciones a la Síntesis Total de Productos Naturales Biológicamente Activos /
New Synthetic Methods and Applications to the Total Synthesis of Biologically Active Natural Products
Recent studies on the development of new synthetic methodology will be presented, along with applications
towards the total synthesis of stereochemically complex, biologically active natural products. The specific
examples highlighted will be selected from our recent efforts on the total synthesis of 13-deoxytedanolide,
amphidinol 3, and amphidinolides C, E and F.
Miguel A Yus
Profesor. Departamento Química Orgánica, Facultad de Ciencias, Universidad de Alicante. Spain
17:00
Nuevas Metodologías basadas en Litiaciones Catalizadas por Arenos / New Methodologies based on an
Arene-Catalyzed Lithiation
The arene-catalyzed lithiation is an efficient methodology in order (1) to prepare organolithium compounds
starting from non-halogenated materials, (2) to reductively open different heterocycles yielding functionalized
organolithium intermediates, (3) to generate organodilithium synthons by heteroatom-lithium exchange, and
(4) to activate other metals, for instance nickel, able to perform the reduction of several organic functionalities.
18:00
Café / Coffee
18:30
Mesa redonda /
Round table
Síntesis de Alto Rendimiento / High Throughput Synthesis
Moderador/Chairperson: Fernando Albericio
Barcelona Biomedical Research Institute, Universidad de Barcelona. Spain
-
José Manuel Villalgordo. VillaPharma
Research S.L. Spain (Moléculas
pequeñas)
-
Joaquín Pastor. Janssen-Cilag. Spain (Diversidad en
síntesis)
-
Rafael Ferritto. Lilly Research
Laboratories. Spain (Automatización en
síntesis)
-
Antoni Molins. Almirall-Prodesfarma. Soain
(Quimioinformática)
Sábado / Saturday / 16
Session 3
Moderador/Chairperson: Rafael Ferrito
Lilly Research Laboratories. Alcobendas, Madrid, Spain
Takashi Takahashi
Professor. Department Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of
Technology. Tokyo, Japan
08:45
Síntesis en Fase Sólida y en Disolución de Muestrotecas de Productos Naturales / Solid and Solution-Phase
Synthesis of Natural Products Libraries
The combinatorial synthesis of a 122-member macrosphelide library using a palladium-catalyzed carbonylation
on a polymer-support and a protected oligosaccharide library by one-pot glycosylation will be presented.
Claudio Palomo Nicolau
Profesor. Departamento Química Orgánica, Facultad de Química, Universidad del País Vasco. San Sebastián,
Spain
09:40
Reacciones Asistidas por Auxiliaries Quirales: Inspiración para el desarrollo de Procesos Catalíticos
Enantioselectivos /
Chiral Auxiliaries-Assisted Reactions: Inspiration for Developing Catalytic Enantioselective Processes
For effective chirality transfer from covalently bonded chiral appendages to the reacting centre there is often
the need to implement concepts such as proximity, concavity, conformational rigidity, and/or high order in
transition state. Aimed at these goals, we have explored the potential of α'-hydroxy ketones for metal
chelation, using the camphor skeleton as the chiral appendage. Thus far, the application of this principle to
aldol, Mannich, Diels-Alder, and related reactions has been pursued. From these designing elements, we have
subsequently developed achiral α '-hydroxy enones as advantageous templates in Lewis acid-catalyzed
enantioselective transformations.
10:35
Coffee / Café
11:00
C. Oliver Kappe
Professor. Department of Chemistry, University of Graz. Austria
Microondas en Síntesis Orgánica / Microwaves in Organic Synthesis
This presentation will describe recent progress in the application of controlled microwave-assisted synthesis
from our laboratory. The subjects covered will include transition metal-catalyzed reactions, heterocycle
preparation, solid-phase synthesis, and the use of polymer-supported reagents for automated library synthesis.
11:55
Mesa redonda /
Round table
Retos para la I+D en España: el caso de la Química Médica / Challenges for R&D in Spain: the case of
Medicinal Chemistry
Moderador/Chairperson: José A Gutiérrez Fuentes Fundación Lilly, Spain
-
Robert W Armstrong. Lilly Research
Laboratories. Indianapolis, USA
-
Miquel A Pericàs. Instituto Catalán de Investigación Química.
Tarragona, Spain
-
Carlos Martínez Alonso. Consejo
Superior de Investigaciones
Científicas, Spain
-
Jorge Martín Juárez. Crystal Pharma / Ragactives, S.A.
Valladolid, Spain
-
Nazario Martín. Real Sociedad Española de Química, Spain
47
13:00
Closure Address / Conferencia de Clausura
Moderador/Chairperson: Julio Álvarez Builla
Javier de Mendoza
Group Leader Institute of Chemical Research of Catalonia (ICIQ). Tarragona, Spain
Autoensamblaje: una Aproximación a la Complejidad Química Inspirada en la Biología / Self-assembly: a Bioinspired approach to Chemical Complexity
The spontaneous self-assembly of molecular building blocks into highly structured, discrete supramolecular
architectures constitutes a bio-inspired approach to chemical complexity, overcoming some of the problems
associated to synthesis based solely on covalent bonds, with the added virtues of economy, cooperativity, selferror-checking, and efficiency, typical for reversible, dynamic processes. We present herein examples of rosette-like
and capsular aggregates based on multiple hydrogen bonds, metal coordination, electrostatic and hydrophobic
forces built around calixarene and related molecular platforms.
13:50
Despedida / Farewell
Julio Alvarez Builla, Fernando Albericio, Jesús Ezquerra,
COMITÉ CIENTÍFICO (ORGANIZADOR):
-
Julio Alvarez Builla
Fernando Albericio
Jesús Ezquerra
Euroforum Infantes. El Escorial, Madrid, Spain
PROMOCION Y PATROCINIO:
Fundación Lilly
CONFERENCIANTES – SPEAKERS:
MT Reetz (G)
B Imperiali (USA)
J Audia (USA)
C Barbas III (USA)
T Welton (UK)
WR Roush (USA)
MA Yus (Sp)
JM Villalgordo (Sp)
J Pastor (Sp)
R Ferrito (Sp)
A Molins (Sp)
T Takahashi (Jp)
C Palomo (Sp)
CO Kappe (Au)
R Armstrong (USA)
MA Pericàs(Sp)
C Martínez (Sp)
J Candil (Sp)
N. Martín (Sp)
J de Mendoza (Sp)
-
La acreditación supondrá la asistencia a todas las sesiones plenarias y, a las mesas redondas
Las conferencias tendrán una duración de 45 minutos y se verán seguidas por un coloquio de 15 minutos, estando abiertas al público en
general.
SECRETARIA
-
Fundación Lilly: C/ Velázquez 94, 6º Izq. 28006 Madrid
Tel: 91 781 50 70-71 / 629 86 14 16
Fax: 91 781 50 79
E-mail: [email protected]
-
www.fundacionlilly.com
Para el SM, las terapias actuales incluyen la dieta y el ejercicio así como determinados agentes indicados para el
tratamiento individual de sus componentes. En el futuro, nuevos avances en el conocimiento de la patología molecular
aflorarán nuevas dianas terapéuticas que permitan prevenir o tratar diferentes aspectos del SM.
En las últimas décadas el SM se ha convertido en un problema de salud pública de primer orden, tanto en sociedades
avanzadas como en aquellas en desarrollo, debido a su alarmante incidencia no solo entre adultos de ambos sexos, sino
también entre la población joven y los niños. Su extensión está directamente asociada con la del estilo de vida
“occidental”, caracterizado por la falta de ejercicio físico, el exceso de ingesta calórica, y consecuentemente, el aumento
del sobrepeso y la obesidad.
Para entender la dimensión del problema, debemos tener en cuenta el impacto negativo que sobre la salud tienen las
dos enfermedades más importantes relacionadas con el SM. Mientras que la diabetes mellitus tipo 2 afecta a más de
120 millones de personas en el mundo, las enfermedades cardiovasculares responden del 30,9% de todas las muertes y
suponen el 10,3% de la carga total de enfermedad. En los EEUU casi un cuarto de la población padece de enfermedad
cardiovascular y no menos de un millón fallecen anualmente por esta causa.
Objetivo de este simposio es proveer a los participantes con información de primera mano y máxima actualidad (desde
la patofisiología molecular a la epidemiología genética) sobre un componente crucial del SM, la obesidad, y también
sobre otros componentes nuevos, tales como las moléculas inflamatorias, el estado pretrombótico, la disfunción
endotelial, o el hígado graso no alcohólico. Hemos realizado un esfuerzo especial para ofrecer una revisión actualizada y
completa en estos campos, enriquecida con diversas contribuciones originales, que confiamos satisfagan a los
participantes en este 8º Simposio Científico Fundación Lilly.
“NUEVAS APROXIMACIONES AL SINDROME METABÓLICO”
 Presidido por Manuel Serrano Ríos, Rafaelle Carraro y José A. Gutiérrez Fuentes
 Celebrado en el Real Colegio María Cristina de San Lorenzo de El Escorial de
Madrid.
"Nuevas aproximaciones al Síndrome Metabólico". Monográfico del 8º Simposio Científico,
publicado como suplemento de la Revista “Endocrinología y Nutrición” Volumen 54,
Monográfico 6, Julio 2007 (ISSN: 1575-0922)
-
Distribución: suscriptores de la revista Endocrinología y Nutrición y a los asistentes al
Simposio. (2.100 ejemplares)
-
49
-PROGRAMA-
Presidencia: Manuel Serrano Ríos, Raffaele Carraro, José F. Caro
Secretaría: José A Gutiérrez Fuentes
Lugar: San Lorenzo de El Escorial, Madrid
Fecha: Noviembre 4 y 5, 2005
Viernes / Friday / 4
08:15
08:45
Opening Keynote
Moderador / Chairperson: Manuel Serrano Ríos, Hospital Clínico San Carlos, Madrid, Spain
09:00
Rafael Carmena
Servicio de Endocrinología, Hospital Clínico, Universidad de Valencia, Spain
Síndrome Metabólico: Una actualización / Metabolic Syndrome: An Update
The metabolic syndrome, in addition to being a precursor to type 2 diabetes, is itself now
recognised as an important risk factor for coronary heart disease (CHD). The recent
consensus of the International Diabetes Federation (IDF) for a new definition of the metabolic
syndrome will be reviewed in this presentation. This definition has central obesity as the core
component based on waist measurement, with differing cut points for different ethnic groups.
The patient must also have at least two abnormalities from: raised fasting glucose,
hypertension, raised TG and lowered HDL-C. In addition, recommendations for the
management of patients with the metabolic syndrome with lifestyle changes and drug therapy
will be presented.
Session 1
09:40
Hígado y Síndrome Metabólico / Liver and Metabolic Síndrome
Moderador / Chairperson: Ricardo Moreno-Otero,Hospital de La Princesa. Madrid, Spain
Norbert Stefan
Dept. Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry,
University of Tübingen, Germany
Determinantes genéticos y ambientales de los lípidos intrahepáticos
Environmental Determinants of Intrahepatic Lipids
/
Genetic and
There is increasing evidence that accumulation of lipids in the liver, the clinical disorder that
is termed non-alcoholic fatty liver disease (NAFLD), is closely associated with the metabolic
syndrome. It is currently under investigation which genetic and metabolic factors predispose
to NAFLD. In a lifestyle intervention program, among others, an imbalance in plasma levels of
adiponectin, and single nucleotide polymorphisms in the adiponectin receptor 1 gene were
found to be regulators of NAFLD.
10:10
Giulio Marchesini
Servizio di Malattie del Metabolismo, "Alma Mater Studiorum", Universita di Bologna, Italy
Hábitos dietéticos, peso corporal y resistencia insulínica en el hígado graso no
alcohólico / Dietary Habits, Body Weight and Insulin Resistance in Non-acoholic
Fatty Liver Disease
Genetic and behavioral factors may contribute to the association of non-alcoholic fatty liver
disease (NAFLD) with insulin resistance. In principles, genetic factors might have a primary
role in lean, non-diabetic subjects, whereas eating habits and sedentary behaviors might
promote hepatic steatosis in the presence of overweight or obesity. Excess body weight
remains a major drive of disease and weight loss is a relevant clue to treatment. Qualitative
aspects of food intake have been less convincingly associated with the extent of hepatic
steatosis. The possibility that defects or abundance of specific dietary components may
facilitate NAFLD and its progression should be addressed in future studies.
51
10:40
11:10
Café / Coffee
Arthur J. McCullough
Division Gastroenterology, Case Western Reserve University, Cleveland, Ohio, USA
Cracterísticas clínicas, diagnóstico e historia natural del hígado graso no
alcohólico / Clinical Features, Diagnosis and Natural History of Non-alcoholic
Fatty Liver Disease
Non-alcoholic steatohepatitis (NASH), the most severe form of non-alcoholic fatty liver
disease (NAFLD) is a progressive fibrotic disease in which cirrhosis and liver-related death
occur in up to 20% and 12% respectively over a 10 year period. In contrast NAFLD has a
benign clinical course.
The demographics of NAFLD and NASH include a wide spectrum of patient profile.
Although the typical patient appears to be an obese, diabetic, hyperlipidemic middle age
female, NAFLD/NASH can be present in any type of patient including children. The
diagnosis can be problematic. Liver enzymes are not particularly helpful. A hepatic
ultrasound is the most useful radiographic test but lacks sensitivity and cannot
differentiate NAFLD from NASH.
NASH, the most severe form of NAFLD, have emerged as a common, clinically important
type of chronic liver disease. The prevalence rates for NAFLD and NASH range between
17-33% for NAFLD and 6-17% for NASH.
These prevalence rates are expected to increase even higher pari passu with the
pandemics of obesity and diabetes worldwide. Clinicians and investigators will need
greater knowledge of this disease which currently impacts all fields of clinical medicine
and will continue to do so with increasing prevalence and adversity to patients.
11:40
Keith D. Lindor
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
Hígado graso no alcohólico: aproximación al tratamiento/ Non-alcoholic Fatty
Fiver: Therapeutic Approach
In this discussion, various therapies for treating nonalcoholic fatty liver will be discussed,
including attempts to reverse associated conditions such as obesity, hyperlipidemia, and
hyperglycemia. Pharmacologic agents designed to address inflammation or oxidant
stress will also be discussed, including insulin sensitizing agents, Betaine, Pentoxifylline,
Vitamin E. Lessons learned from a large-scale randomized trial of ursodeoxycholic acid
which provides information about the natural history of nonalcoholic fatty liver disease
and points out some of the pitfalls in interpreting data from uncontrolled pilot studies will
also be discussed.
12:10
12:45
13:45
Session 2
15:15
Seminario 1
Seminario 2
Almuerzo / Lunch
Endotelio, trombosis y Síndrome Metabólico / Endothelium, Thrombosis and
Metabolic Syndrome
Moderador / Chairperson: Diego Rodríguez Puyol
H. U. Príncipe de Asturias, Alcalá Henares, Madrid, Spain
José M. Fernández Real
Unit of Diabetes, Endocrinology and Nutrition, Hospital Universitari Girona, Spain
Resistencia insulínica y Síndrome inflamatorio cardiovascular crónico /Insulin
Resistance and Chronic Cardiovascular Inflammatory Syndrome
In the last years, type 2 diabetes is increasingly recognized as an inflammatory state.
Decreased insulin action was proposed as the triggering factor of the different
components of the metabolic syndrome, which are directly linked to cardiovascular
disease. Insulin resistance and cardiovascular disease share common pathophysiological
mechanisms, as the chronic activation of the innate immune system. This system
constitutes the first line of body’s defense and is constituted by different barriers
(epithelia, adipose tissue), and different blood and tissue components as macrophages,
and neutrophils. Acute phase proteins and cytokines are produced in response to
different aggressions as infections and traumatisms. The aim of this response is to
eradicate these agents, to repair the harmed tissues, and, through increased insulin
resistance, to optimize the energetic substrates.
15:45
Paresh Dandona
Millard Fillmore Hospital, University of Buffalo, New York, USA
Diabetes y Endotelio/ Diabetes and the Endothelium
Recent research has shown that insulin is a vasodilator and that it causes a secretion of NO
from the endothelium. It has also been shown that insulin suppresses inflammatory
mediators from the endothelium and circulating MNC. In addition, it suppresses
atherogenesis in the apoEº mouse and that interference with its signal results in
atherogenesis. Clearly, insulin has an anti-inflammatory and possibly an anti-atherogenic
and cardioprotective effect. A re-interpretation of the metabolic (insulin resistance)
syndrome in view of these novel actions of insulin would explain several clinical features of
the metabolic syndrome related to its cardiovascular complications.
16:15
Marie Christine Alessi
Laboratoire d'ematologie, INSERM UMR626, UFR de Medecine, Universite de la
Mediterranee, Marseille, France
Fibrinolisis y Síndrome Metabólico / Fibrinolysis and Metabolic Syndrome
Increased plasma Plasminogen Activator Inhibitor type 1 (PAI-1) levels has, since a long
time, been described in obese insulin resistant patients. This could be considered as a
contributing factor to elevated risk of coronary heart disease in obese insulin resistant
people. It appears likely, that the relationship between obesity, insulin resistance, and PAI1 may depend at least in part on the increased production of PAI-1 by adipose tissue. PAI-1
is involved in tissue remodelling, therefore it has been speculated that the increased
expression of PAI-1 in obesity influences the remodeling and expansion of adipose tissue.
Finding using PAI-1 transgenic- suggest that PAI-1 produced by the adipose tissue could be
directly involved in etiopathogenesis of obesity and insulin resistance.
16:45
Angelo Avogaro
Department of Clinical and Experimental Medicine, University of Padova, Italy
Disfunción endotelial en el Síndrome Metabólico / Endothelial Dysfunction in the
Metabolic Syndrome
The aim is to describe the pathophysiology of endothelial dysfunction in the Metabolic
Syndrome, and to outline the mechanisms that, in each component of the syndrome, lead
to the endothelial damage.
17:15
17:45
18:15
Café / Coffee
Seminario 1
Seminario 3
Sábado / Saturday / 5
Session 3
09:00
Obesidad y Síndrome Metabólico / Obesity and Metabolic Syndrome
Moderador / Chairperson: Pedro González Santos
Hospital Clínico de Málaga. Spain
I Sadaf Farooqi
University Departments of Medicine and Clinical Biochemistry, Cambridge Institute for
Medical Research, Addenbrooke's Hospital, Cambridge, UK
Susceptibilidad genética y obesidad / Genetic Susceptibility and Obesity
In the last few years, we and others have described six human disorders of energy
balance that arise from genetic defects. The first monogenic human obesity syndrome we
reported was congenital leptin deficiency which can be treated with recombinant human
leptin. We have recruited over 1700 severely obese children to the Genetics of Obesity
Study (GOOS). Using a candidate gene approach, we have identified loss of
function mutations in the melanocortin 4 receptor (MC4R), which cause a dominantly
inherited syndrome that accounts for up to 5% of patients with severe, early-onset
obesity. These studies have highlighted the role of leptin and the melanocortin axis in
humans and the characterization of these syndromes has shed light on the molecular and
physiological mechanisms underlying the regulation of appetite and body weight.
53
09:30
Peter Arner
Department of Medicine at Karolinska Institute, Huddinge University Hospital, Sweden
Complicaciones metabólicas asociadas a la obesidad: un problema del tejido
adiposo / Metabolic Complications Associated with Obesity: An Adipose Tissue
Problem
Adipose tissue secretes many molecules that may influence insulin sensitivity and cause a
metabolic syndrome phenotype. Two adipocyte specif factors are adiponectin, which
modulates insulin sensitivity and fatty acids which influence insulin action and secretion
and also influence lipid and carbohydrate metabolism. The development of upper-body
obesity leads to an inflammatory state of adipose tissue which increases fatty acid
production and inhibits adiponectin production so that insulin resistance develops. An
adipocyte-specific gene, CIDEA, protects adipose tissue from the inflammatory effects.
10:00
10:30
Coffee / Café
Miguel A. Rubio
Servicio de Endocrinología y Nutrición, Hospital Clínico San Carlos, Madrid, Spain
La experiencia del Estudio DRECE / The DRECE Study Experience
The Diet and Risk of Cardiovascular Diseases in Spain Study (DRECE) is a prospective
study designed to evaluate the relation among life habits, mainly dietary, and
cardiovascular diseases prevalence in Spain. More than 5000 persons, both sexes and age
matched 5-59 years, representative of the Spanish population, are being followed from
1990. Results on Metabolic Syndrome prevalence among DRECE cohort will be
commented. Also its correlation with other cardiovascular risk factors will be considered.
11:00
José F. Caro
Endocrine Research / Clinical Investigation, Eli Lilly, Indianapolis, USA
Sobre el intento para detener la progresión del Síndrome Metabólico / On the
Trail to Arrest the Progression of the Metabolic Syndrome
The Metabolic Syndrome comprises a cluster of syndromes belonging to a group called
“Complex Diseases” (the phenotype of multiple genes interacting with the environment,
i.e., diabetes, hypertension, obesity, atherosclerosis, etc.). The treatment of the
Metabolic Syndrome is directed toward the identification of each risk factors and
implementation of its treatment following current guidelines. These accepted
management principles will not be discussed here. Rather, proof-of-concept experiments
demonstrating the feasibility of arresting the progression of the Metabolic Syndrome will
be the focus. Furthermore, challenges and opportunities for the future will be discussed.
It is clear, however, that only a multi-pronged approach may modify the current trends in
the Metabolic Syndrome. A pharmacological solution is only part of the overarching
strategy… and it’s not without difficulties.
11:30
12:00
Seminario 2
Seminario 3
Closure Keynote
Moderador / Chairperson: José A. Gutiérrez Fuentes, Fundación Lilly, Spain
13:00
John Yudkin
Diabetes and Cardiovascular Disease Academic Unit, Department of Medicine, Royal Free
and University College Medical School, London, UK
Nuevas formas de entender la relación entre el Síndrome Metabólico y la
Enfermedad Cardiovascular/ New Understandings of the Links between Metabolic
Syndrome and Vascular Disease
Insulin resistance is frequently associated with obesity, particularly an excess of central
fat. Many of the features which have been ascribed to the metabolic syndrome are more
common in obese subjects, including microalbuminunria and endothelial dysfunction. More
recently, features of low-grade inflammation have been associated with obesity. Adipose
tissue generation of adipocytokines such as tumour necrosis factor-α, may act
predominantly in autocrine or paracrine fashion, others are released into the systemic
circulation, acting as signalling molecules to remote tissues, including liver, skeletal muscle
and endothelium. Perivascular fat may also contribute both to insulin resistance and to
vascular disease.
13:40
José A Gutiérrez Fuentes, Manuel Serrano Ríos y Raffaele Carraro
(*) SEMINARIOS
SEMINARIO 1
Ponente: Juan Ascaso. Servicio de Endocrinología, Hospital Clínico Universitario de
Valencia, Spain
Síndrome Metabólico: Criterios de definición y diagnóstico / Metabolic
Syndrome: Definition and Diagnostic Criteria
Existen numerosas definiciones de síndrome metabólico lo que ha conducido a
confusión. El SM es el conjunto de alteraciones metabólicas, inflamatorias y vasculares
relacionadas con la resistencia a la insulina y sus principales componentes son
dislipemia, hiperglucemia, inflamación crónica y la asociación de obesidad. Su riesgo
cardiovascular es alto.
SEMINARIO 2
Ponente: Raffaele Carraro. Servicio de Endocrinología y Nutrición, Hospital de La
Princesa, Madrid, Spain
Síndrome Metabólico: Evaluación del riesgo cardiovascular / Metabolic
Syndrome: Cardiovascular Risk Evaluation
Although there is no doubt that the metabolic syndrome (MetS) is a condition that
constitutes an important cardiovascular (CV) risk factor, several questions are still open
to debate. First, which is the best MetS definition for CV risk assessment, and is there a
better combination of its constituting factors to such a purpose? Is MetS as a whole a
more powerful criterion in predicting CV events than is the sum of the risk of its
components? Finally, does MetS detect CV risks not captured by other prediction models
such as the Framingham equation?
SEMINARIO 3
Ponente: Pedro Conthe. Servicio de Medicina Interna, Hospital Universitario Gregorio
Marañón, Madrid, Spain
Síndrome Metabólico: Tratamiento / Metabolic Syndrome: Treatment
Se discuten los aspectos terapéuticos de un caso clínico de un paciente con Síndrome
Metabólico definido a lo largo de la historia natural de la enfermedad. De forma
interactiva se plantean las prioridades terapéuticas del caso a la luz de las
recomendaciones vigentes referidas a las medidas generales y al manejo terapéutico de
los componentes individuales
Viernes 4
Sábado 5
12:45
SEMINARIO 1
18:15
SEMINARIO
1
SEMINARIO 2
PROMOCION Y PATROCINIO:
12:00
SEMINARIO 3
SEMINARIO
2
SEMINARIO 3
Fundación Lilly
COMITÉ CIENTÍFICO (ORGANIZADOR):José A Gutiérrez Fuentes, Manuel Serrano Ríos, Raffaele Carraro
Manuel Serrano Rios
Rafael Carmena
Ricardo Moreno-Otero
Norbert Stefan
Giulio Marchesini
Arthur J. McCullough
Keith D. Lindor
Diego Rodríguez Puyol
José M. Fernández Real
Paresh Dandona
Marie Christine Alessi
Angelo Avogaro
I Sadaf Farooqi
Pedro González Santos
Peter Arner
Miguel A Rubio
José F. Caro
John Yudkin
Juan Ascaso
Raffaele Carraro
Pedro Conthe
La acreditación supondrá la asistencia a todas las sesiones plenarias y, al menos a dos de los seminarios
Las conferencias tendrán una duración de 30 minutos
Al final de cada mesa habrá una discusión de 30 minutos
SECRETARIA
Fundación Lilly:
C/ Velázquez 94, 6º Izq. 28006 Madrid
Tel: 91 781 50 70-71 / 629 86 14 16
Fax: 91 781 50 79
E-mail: [email protected]
55
En el campo oncológico existen diversas áreas de interés entre las que se incluyen aspectos relacionados con la salud
pública, así como el cáncer como enfermedad responsable de una elevada proporción de morbilidad y mortalidad.
El cáncer es una enfermedad con una fisiopatología compleja y múltiples mecanismos de acción, que requieren de una
enorme inversión en investigación, tanto a nivel de capital humano como económico. En la actualidad, la tendencia más
extendida está basada en la coordinación y creación de proyectos internacionales y multidisciplinares diseñados para
resolver los desafíos y las metas de adquirir el conocimiento de los mecanismos de la carcinogénesis y de sus
condicionantes genéticos, el descubrimiento de nuevas estrategias preventivas y terapéuticas, y la creación de servicios
de ayuda a los clínicos, que necesitan información y las pautas para el tratamiento de los pacientes.
La iniciación y la progresión del cáncer están controladas por la adquisición de numerosos defectos genéticos y
epigenéticos. Las aberraciones epigenéticas son potencialmente reversibles. A diferencia de los defectos genéticos, que
son virtualmente irreversibles, los cambios epigenéticos son susceptibles de ser revertidos, de manera que a priori la
población de células malignas podría recuperar un fenotipo más parecido al de las células normales. Con el
advenimiento de numerosos fármacos que están dirigidos contra enzimas específicas implicadas en la regulación
epigenética de la expresión, ha comenzado a desarrollarse un tipo de terapia está emergiendo como una estrategia
eficaz y valiosa en el desarrollo de quimioterapia así como el quimioprevención del cáncer.
Actualmente, la investigación en cáncer se fundamenta en conceptos modernos que motivarán la incorporación de
científicos experimentados y atraerán a aspirantes más jóvenes a que encuentren una oportunidad de adquirir
formación.
Aspiramos a contribuir a este esfuerzo y a los nuevos proyectos que se generarán, así como a ayudar a atraer la
atención pública y fondos de inversión privados para la investigación de cáncer en España, puesto que la oncología es
una disciplina importante y emocionante.
Comité Científico Organizador, marzo de 2006
“EPIGENÉTICA DEL CÁNCER: DESDE EL CONOCIMIENTO MOLECULAR AL
TRATAMIENTO"
 Presidido por Manel Esteller, Peter A. Jones y Carlos Caldas.
 Poster: 37 admitidos
 Fecha: 16, 17 y 18 de marzo de 2006.
57
-PROGRAMA-
Presidencia / Chairmen: Peter A. Jones, Carlos Caldas & Manel Esteller
Secretario / Secretary: José A. Gutiérrez Fuentes
San Lorenzo de El Escorial, Madrid
Marzo / March 16, 17 & 18, 2006
Jueves / Thursday / 16
08:15
08:30
Mariano Barbacid. CNIO; Madrid, Spain
José A. Gutiérrez-Fuentes. Fundación Lilly; Spain
08:45
CONFERENCIA DE APERTURA / KEYNOTE ADDRESS
Moderador / Chairperson: Mariano Barbacid
Paul A. Marks
Memorial Sloan-Kettering Cancer Center; New York, USA
Los inhibidores de las deacetilasas de histonas: mecanismo de acción y desarrollo de fármacos anticáncer
/Histone Deacetylase Inhibitors: Mechanisms of Action and Development as Anti-Cancer Agents
(+info)
Sesión 1
09:30
Among the most studied epigenetic mechanisms of regulation of gene expression is the acetylation-deacetylation
of histone proteins controlled by histone deacetylase (HDAC0 and histone acetyltransferase (HAT) activities. In
addition to histones, HDAC targets include transcription factors, proteins regulating cell growth and death
pathways and proteins regulating cell migration, angiogenesis and cell adhesion. The mechanisms of action of the
HDAC inhibitor (HDACi), SAHA, and related compound discovered in our laboratory. SAHA has been in Phase I/II
clinical trials and shown significant anti-cancer activity in patients with hematologic and solid malignancies at well
tolerated doses.
http://www.mskcc.org/mskcc/html/10595.cfm
METILACIÓN DEL ADN, CÉLULAS TUMORALES Y EL METILOMA HUMANO /
DNA METHYLATION, CANCER CELLS AND THE HUMAN METHYLOME
Moderador / Chairperson: Juan Carlos Lacal. Instituto de Investigaciones Biomédicas, CSIC, Madrid, Spain
Peter A. Jones
USC/Norris Comprehensive Cancer Center; Los Angeles, USA
Alteración del epigenoma en cáncer / How the epigenome gets altered in cancer
The covalent modification of DNA cytosine residues and associated histone proteins play a major role in the
stability and heritability of epigenetic states. These covalent modifications of DNA and proteins interact with the
chromatin remodeling apparatus to regulate the interaction of transcription factors with DNA thus contributing to
stable patterns of gene expression. CpG islands are usually unmethylated in normal tissues except for genes
located on the inactive X-chromosome, imprinted genes and some tissue specific genes. Histones are marked by
covalent modifications and we have found that active marks are highly localized to the start sites of human genes.
These patterns of modification are altered during the formation of human cancer so that CpG islands become
abnormally methylated, histones become modified with repressive marks and we have recently discovered that
nucleosomal remodeling occurs, resulting in the silencing of genes. Focal changes such as these often occur in the
presence of genomic cytosine hypomethylation and histone hyperacetylation showing a major imbalance in
epigenetic programming. Epigenetic silencing can serve as a therapeutic target for epigenetic therapies which
seek to reverse silencing and restore more normal gene expression patterns to cancer cells. To date, the focus has
mainly been on the reactivation of protein coding genes yet we have found that micro RNAs can also become
abnormally silenced in human cancer cells by such chromatin modifications. Reactivating micro RNAs could
potentially yield a novel therapeutic strategy in the treatment of cancer.
http://ccnt.hsc.usc.edu/about/leadership/jones.html
59
10:15
Stephen B. Baylin
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Baltimore, USA
El papel clave del silenciamiento genético en las etapas más tempranas del cáncer /
The key role for epigenetic gene silencing in the earliest stages of neoplasia
In this presentation, I will express the concept that epigenetic changes, and especially aberrant DNA
hypermethylation of key gene promoters, play a critical role in the earliest stages of neoplastic evolution.
These changes may, actually, drive such stages even before critical gene mutations emerge through addicting
cells to signal pathway abnormalities which foster abnormal clonal cell expansion. A key to understanding why
these epigenetic changes arise is to consider the concept of the cancer DNA hypermethylome , including the
numbers of genes involved, and programs which might underlie the silencing of such genes. In turn, a key to
this understanding relates to defining the chromatin construction of involved gene promoters and the
association of these chromatin patterns with the associated DNA methylation. Current data concerning these
issues will be discussed.
http://www.hopkinsmedicine.org/graduateprograms/cmm/baylin.html
Café / Coffee
Sesión de Paneles I / Poster Session I
11:00
11:30
Manel Esteller
CNIO; Madrid, Spain
Epigenética del cáncer: desde el conocimiento al tratamiento /
Cancer epigenetics: From knowledge to therapy
The recognition of epigenetic defects in all types of cancer has represented a revolutionary achievement in
cancer research in recent years. DNA methylation aberrant changes (global hypomethylation and CpG island
hypermethylation) were among the first events to be recognized. Over recent years, a better understanding of
the machinery that connects DNA methylation, chromatin and transcriptional activity, in which histone
modifications stand in a key position, has been achieved. The identification of these connections has
contributed to developing novel therapies that can reverse epigenetic defects in cancer cells.
http://www.cnio.es/es/programas/prog503.asp
12:15
Andrew P. Feinberg.
Johns Hopkins University School of Medicine; Baltimore, USA
La epigenética en la etiología del cáncer / The epigenetics of cancer etiology
Cancer epigenetics has been limited by questions of cause and effect, since epigenetic changes can arise
secondary to the cancer process and its associated widespread changes in gene expression. We have focused
on identifying epigenetic changes in normal cells that predispose to cancer. One line of investigation has been
on the disorder Beckwith-Wiedemann syndrome (BWS). We have also developed an animal model for the role
of loss of imprinting (LOI) of IGF2 in cancer, showing that it cooperates with Apc mutations to increase cancer
frequency, consistent with human data suggesting a several fold increased cancer risk for this common
epigenetic variant in the adult population. These data suggest that a major component of cancer risk involves
epigenetic changes in normal cells that increase the probability of cancer after genetic mutation.
http://www.mbg.jhmi.edu/FacultyDetails.asp?PersonID=585
13:00
Christoph Plass
The Comprehensive Cancer Center, The Ohio State University; Columbus, USA
La metilación del ADN y el genoma del cáncer /
DNA methylation and the cancer genome
The cancer genome is characterized bi genetic and epigenetic alterations. DNA methylation is one of the
epigenetic modifications that is modified in the cancer genome. Both the loss of global DNA methylation levels
and as well as the gain of aberrant DNA methylation in regulatory sequences has been described. Here we will
discuss our current knowledge on CpG Island methylation and provide evidence for fine tuned “micro” patterns
of altered DNA methylation that modulate gene expression.
http://www.cancergenetics.med.ohio-state.edu/2741.cfm
13:45
Almuerzo / Lunch
Sesión 2
15:00
TRATAMIENTO DE LOS PACIENTES ONCOLÓGICOS MEDIANTE FÁRMACOS DESMETILANTES DEL ADN /
CLINICAL TREATMENT OF CANCER PATIENTS BY DNA DEMETHYLATING AGENTS
Moderador / Chairperson: Hernán Cortés Funes. Servicio de Oncología, Hospital 12 de Octubre; Madrid, Spain
Robert Brown
Cancer Research UK Beatson Laboratories; Glasgow, UK
Modulación de la resistencia a los fármacos mediante tratamientos epigenéticos / Modulation of drug
resistance by epigenetic therapies
The acquisition of drug resistance is a major problem in the successful treatment of cancer. There is increasing
evidence for a role for aberrant epigenetic regulation of gene expression during the acquisition of resistance to
cytotoxic chemotherapies. I will describe preclinical models and clinical trials that examine the potential of
DNMT and HDAC inhibitors to chemosensitise solid tumours. Central to these studies is the use of biomarkers,
both as pharmacodynamic markers of drug efficacy and for enrichment of patients who may benefit from these
epigenetic therapies.
http://www.beatson.gla.ac.uk/research/glasgow.html?topic_id=21
15:45
Michael Lubbert
University of Freiburg Medical Center; Freiburg, Germany
Agentes desmetilantes a dosis bajas: Una opción de tratamiento no intensivo para pacientes mayores con neoplasia
mieloide / Low-dose demethylating agents: A non-intensive treatment option for older patients with myeloid
neoplasia
The large majority of myeloid neoplasias do not carry the bcr-abl rearrangement or another activated tyrosine kinase
presently amenable to pharmacological inhibition. Thus no targetted therapy is established for the these often elderly
patients with inherent poor tolerance to aggressive chemotherapy (due to reduced performance status, comorbid
conditions etc.). Demethylating agents have been developed at schedules allowing non-intensive treatment, with very
limited non-hematological toxicity, of myelodysplasia (5-azacytidine/Vidaza, Decitabine) and AML (Decitabine). Agents
with demethylating activity have be shown by systematic cytogenetic analyses to be at least partially selective for the
abnormal, clonal hematopoetic cells of MDS, while myelosuppressive effects upon normal hematopoiesis, at least at
the doses studied so far, are much less marked. Thus both the response rates and favorable toxicity profile are very
encouraging and further development of these drugs includes combinations e.g. with histone deacetylase inhibitors.
http://www.ukl.uni-freiburg.de/med/med1/abteilung/oa_atz/lebenslaeufe/dr_luebbert.htm
16:30
17:00
Café / Coffee
Sesión de Paneles I / Poster Session I
Jean-Pierre J. Issa
University of Texas, MD Anderson Cancer Center; Houston, USA
¡La hipometilación funciona como terapia! / Hypomethylation therapy works!
The FDA approval of 5-azacytidine for the treatment of MDS and the favorable clinical results obtained with 5aza-2’-deoxycytidine (DAC) in various hematologic malignancies transform hypomethylation therapy of cancer
from concept to clinical reality. Mechanism-based optimization of dose and schedule led to a substantial
improvement in the clinical results, such that more than half the patients with myeloid malignancies show
dramatic responses to this agent. Responses require hypomethylation and are associated with induction of P15
expression. Genetic markers suggest that responses relate to early differentiation and late clearing of the
malignant clone, all suggestive of an epigenetic mechanism of action. Histone deacetylase inhibitors are also
showing clinical activity, albeit lower than that of hypomethylating drugs. The future of epigenetic therapy will
clearly entail combinations of drugs to (i) enhance gene reactivation and (ii) exploit gene reactivation, and
clinical trials of such approaches are ongoing.
http://www.mdanderson.org/departments/leukemia/display.cfm?id=C646ED82-D121-11D480FD00508B603A14&method=displayFull&pn=0F815FDC-C623-11D4-80FB00508B603A14
17:45
Pere Gascón
Servicio de Oncología, Hospital Clinic; Barcelona, Spain
La epigenética y el microambiente tumoral /
Epigenetics and the tumoral microenvironment
There is a growing body of evidence that normal cells effectively restrict malignant behaviour, and that such forces
must be controlled in order to establish a tumour. Persistent disruption of the microenvironment such in inflammation
or pathological tissue states may compromise its ability to suppress carcinogenesis. Recent publications have shown
that stromal cells and their products can cause the transformation of adjacent cells through transient signalling that
leads to the disruption of tissue homeostatic regulation. It is now well established that tumour progression requires a
continually evolving network of interactions between neoplastic cells and tissue microenvironment (stromal cells and
extracellular matrix-ECM).
It is postulated, that only when the disruption of tissue homeostasis becomes chronic such as in persistent
inflammatory conditions, continual up regulation of enzymes such as matrix metalloproteases by stromal fibroblasts
can disrupt the ECM, and invading immune cells, such as macrophages, can overproduce factors that promote
abnormal proliferation. These abnormal interactions might lead to genomic instability within normal tissue cells and
the acquisition of tumorigenic potential. At this point, the tumour has become its own organ. However, some cells with
tumorigenic genotype can become phenotypically normal if the context is appropriately manipulated. In other words,
the phenotype can override the genotype. Under these premises, one can contemplate therapeutic strategies where
the new agents will target the tumour microenvironment.
http://www.oncopress.net/especialistas/vespecialista.asp?id=20
61
Viernes / Friday17
Sesión 3
09:00
MODIFICACIÓN DE LAS HISTONAS Y LA CROMATINA Y SUS MODIFICADORES / HISTONE AND CHROMATIN
MODIFICATIONS AND THEIR MODIFIERS
Moderador / Chairperson: Eugenio Santos. Instituto de Biología Molecular y Celular del Cáncer; Salamanca,
Spain
Tony Kouzarides
Wellcome Trust / Cancer Research, Gurdon Institute; London, UK
Las modificaciones de la cromatina y sus funciones /
Chromatin modifications and their functions
Chromatin modifications play an important role in many biological processes and their pathways are
disrupted in cancer. We are trying to identify and characterize new modifications that affect chromatin. One
such new pathway is the isomerisation of proline residues within histone H3. Analysis of this new pathway
reveals that it regulates transcription by offering the methylation of histone H3 at lysine 36.
http://www.gurdon.cam.ac.uk/~kouzarideslab/
09:45
Rob Martienssen
Cold Spring Harbor Laboratory; Cold Spring Harbor, New York, USA
Dando sentido al ARN heterocromático / Making sense of heterochromatic RNA
Heterochromatic (junk) RNA is widespread and processed by RNAi, especially from tandem repeats. In
fission yeast, PolII and a putative 3'end processing complex are required for silencing and RNAi. In
Arabidopsis, the SWI/SNF remodeler DDM1 targets DNA methylation and histone H3 K9 methylation to
transposons, via siRNA. DDM1, HDAC and MET1 (dnmt1) can silence transposons independently of RNAi, but
re-silencing requires siRNA in cis. Transposons and heterochromatic repeats can regulate neighboring genes.
http://www.cshl.edu/public/SCIENCE/martien.html
10:30
Thomas Jenuwein
Research Institute of Molecular Pathology –IMP-; Vienna, Austria
Control epigenético mediante la metilación de las histonas /
Epigenetic control by histone methylation
Epigenetic mechanisms control eukaryotic development beyond DNA-stored information. DNA methylation,
histone modifications and variants, nucleosome remodelling and non-coding RNAs all contribute to the
dynamic 'make-up' of chromatin under distinct developmental options. In particular, the great diversity of
covalent histone tail modifications has been proposed to be ideally suited for imparting epigenetic
information. While most of the histone tail modifications represent transient marks at transcriptionally
permissive chromatin, some modifications appear more robust at silent chromatin regions where they index
repressive epigenetic states with functions also outside transcriptional regulation. Under-representation of
repressive histone marks could be indicative of epigenetic plasticity in stem, young and tumor cells, while
committed and senescent (old) cells often display increased levels of these more stable modifications. We
analyzed profiles of normal and aberrant histone lysine methylation patterns, as they occur during the
transition of an embryonic to a differentiated cell or in controlled self-renewal vs. pro-neoplastic or
metastatic conditions. Elucidating these histone modification patterns promises to have important
implications for novel advances in stem cell research, nuclear reprogramming and cancer, and may offer
novel targets for the combat of tumor cells, potentially leading to new diagnostic and therapeutic avenues in
human biology and disease.
http://www.imp.univie.ac.at/jenuwein/jen_hp.html
11:15
11:45
Coffee / Café
Sesión de Paneles II / Poster Session II
Yi Zhang
University of North Carolina at Chapel Hill; North Carolina, USA
La metilación de las histonas en la regulación de la transcripción y el cáncer / Histone methylation in
transcription regulation and cancer
Chromosomal translocation is a common cause of leukemia. However, the underlying mechanism for most
leukemias involving chromosomal translocation is not clear. We demonstrate that the H3K79
methyltransferase hDOT1L contributes to leukemogenesis of several fusion proteins by mis-targeted to
different Hox genes.
http://www.med.unc.edu/~zhangyi/lab.htm
12:30
Yang Shi
Harvard Medical School; Boston, USA
Regulación de la metilación de las histonas mediante desmetilasas /
Regulation of histone methylation by demethylases
Histone methylation was considered a “permanent” modification until the discovery of LSD1. Together with
the recent finding of JHDM1, these results suggest that demethylases are likely to represent a general
mechanism that provides dynamic regulation of histone methylation. In this presentation, I will discuss our
investigation of LSD1 in S. pombe and our efforts of identifying new histone demethylases.
http://www.hmcnet.harvard.edu/pathol/labs/shi/statsShi.html
13:15
Almuerzo / Lunch
Sesión 3 (cont.)
MODIFICACIÓN DE LAS HISTONAS Y LA CROMATINA Y SUS MODIFICADORES / HISTONE AND CHROMATIN
MODIFICATIONS AND THEIR MODIFIERS
Moderador / Chairperson: Juan Angel Velasco (Lilly Research Labs., Alcobendas, Spain)
15:00
Peter B. Becker
Adolf-Butenandt Institut; Munich, Germany
Remodelación del nucleosoma en el desarrollo temprano de Drosophila melanogaster /
Nucleosome remodeling during early development of Drosophila melanogaster
ATP-dependent nucleosome remodeling emerges as a principal mechanism underlying all dynamic
transitions of chromatin structure. The considerable number of nucleosome remodeling ATPases and their
association with regulatory subunits leads to enzymes with cell-type specificity and functional diversification.
Studies in the Drosophila model reveals crucial functions for ISWI-containing remodeling complex during the
earliest embryonic developmental stages.
http://molekularbiologie.web.med.uni-muenchen.de
15:45
Genevieve Almouzni
CNRS / Institut Curie; Paris, France
Propagación del estado epigenético durante el ensamblaje de la cromatina / Propagation of epigenetics
states at the level of chromatin assembly
Heterochromatin is thought to play a critical role for centromeric function and gene silencing. In mouse cells,
we found that centric and pericentric repeats on the chromosomes (corresponding to minor and major
satellites) have distinct heterochromatic properties in the nucleus. These domains display specific higher
order organisation and replicate asynchronously. Furthermore, chromatid cohesion is sustained for a longer
time in major satellites compared to minor satellites. We thus define functionally independent centromeric
subdomains, which spatio-temporal isolation is proposed to be important for centromeric cohesion and
dissociation during chromosome segregation.
We then investigated how the complex organization of HP1-rich pericentric domains is reproduced at each
replication cycle in mouse cells. We find that replication occurs mainly at the surface of these domains
where both PCNA and CAF-1 are located. Pulse-chase experiments combined with high resolution analysis
and 3D modeling show that within 90 minutes newly replicated DNA become internalized inside the domain.
Remarkably, during this time period, a specific subset of HP1 molecules (α and γ) coinciding with CAF-1 and
replicative sites is resistant to RNAse treatment. This replicative pool of HP1 molecules disappears
completely following p150CAF-1 siRNA treatment. We conclude that during replication, the interaction of
HP1 with p150CAF-1 is essential to promote delivery of HP1 molecules to heterochromatic sites. We will
discuss our recent data on this topic.
http://www.curie.fr/recherche/themes/detail_equipe.cfm/lang/_fr/id_equipe/4.htm
16:30
Maarten van Lohuizen
The Netherlands Cancer Institute; Amsterdam, The Netherlands
Represores de Polycomb que controlan el devenir de las células madre: Implicaciones en el cáncer y el
desarrollo / Polycomb repressors controlling stem cell fate: Implications for cancer and development
Repressive Polycomb-group protein complexes are involved in the dynamic maintenance of proper gene
expression patterns during development, acting at the level of chromatin structure. As such, they are
important controllers of cell fate. In particular, recent experiments have demonstrated a crucial role for
Polycomb repressors in controlling the self-renewal capacity of stem cells and cancer stem cells. When
deregulated, these master switches of gene expression are strongly implicated in formation of a diverse set
of cancers. I will discuss recent examples highlighting the emerging molecular mechanisms by which
Polycomb repressors regulate stem cell fate and may contribute to cancer formation.
http://www.onderzoekinformatie.nl/nl/oi/nod/onderzoeker/PRS1242993/
63
Café / Coffee
Sesión de Paneles II / Poster Session II
17:15
17:45
Carlos Caldas
Cancer Genomics Program, University of Cambridge; Cambridge, UK
Expresión diferencial de los genes modificadores de histonas en tumores humanos sólidos: Dianas para el
diagnóstico y la terapia / Differential expression of histone modifier genes in human solid tumors: Targets
for diagnosis and therapy
Histone modifier enzymes are responsible for modulating histone tail modifications and regulate gene
expression at the chromatin level. The characterization of patterns of expression of genes encoding histone
modifiers (using QRT-PCR and expression arrays) is an essential first step in the understanding of their
biology and in their development as diagnostic and therapeutic targets.
www.hutchison-mrc.cam.ac.uk/
18:30
Eric Miska
Wellcome / CRC Institute, University of Cambridge; Cambridge, UK
Papel de los microARNs en el desarrollo de C. elegans y en el cáncer humano /
Roles of microRNAs in C. elegans development and human cancer
In the last five years microRNAs (miRNAs) have emerged from the obscurity of C. elegans heterochronic
heterochronic pathway to a new paradigm of gene regulation in plants an animals. Currently, microRNAs
represent 2% of all known human genes. Very little is known about their biological function.
We have taken a functional genomics approach to study the roles of microRNAs in C. elegans development.
We have generated deletion
strains corresponding to 96 microRNAs, covering the majority of known
microRNA genes. We will present an overview of the classes of mutant
phenotypes we have observed. One focus will be the issue of redundancy within families of microRNA genes.
This study represents the first comprehensive analysis of microRNA function.
We are also interested in the roles of short RNAs in the control of gene expression at the transcriptional
level. We will present our work on how these short RNAs work together with a set of argonaute proteins to
control germline development in C. elegans.
http://www.gurdon.cam.ac.uk/groups/miska.html
Sesión 4
09:00
TRATAMIENTO DEL CÁNCER CON INHIBIDORES DE LAS DEACETILASAS DE HISTONAS Y OTRAS TERAPIAS
TRANSCRIPCIONALES /
CLINICAL TREATMENT OF CANCER BY INHIBITORS OF HISTONE DEACETYLASES AND OTHER
TRANSCRIPTIONAL THERAPIES
Moderador / Chairperson: Alfredo Carrato Mena. Hospital Universitario de Elche; Alicante, Spain
Francesco Lo Coco
Universita Tor Vergata; Rome, Italy
Datos preliminares del tratamiento de leucemia mieloide aguda avanzada con ácido valpróico / Preliminary
experience on treatment of advanced acute myeloid leukemia with valproic acid
A pilot study was carried out in 8 high-risk AML patients not eligible for intensive therapy to asses the
biological and therapeutic activities of the HDAC inhibitor VPA used to remodel chromatin, followed by the
addition of ATRA, to activate gene transcription and differentiation in leukemic cells. We found that
VPA/ATRA treatment is well tolerated and induces phenotypic changes of AML blasts through chromatin
remodelling. Further studies are needed to evaluate whether VPA-ATRA treatment by reprogramming
differentiation of the leukemic clone might improve the response to chemotherapeutic agents in leukemia
patients.
http://www.med.uniroma2.it/facolta/corpo_docente/associati/lococo.html
09:45
Miguel Ángel Sanz
Hospital Universitario La Fe; Valencia, Spain
Tratamiento de las neoplasias mieloides con terapias transcripcionales / Treatment of myeloid
malignancies by transcriptional therapies
Understanding the basic cellular and molecular biology of leukemia is crucial to the development of targeted
therapies. Epigenetic mechanisms underlying leukemogenesis have recently received much attention as
potential therapeutic targets. Two major mechanisms of aberrant gene silencing have been implicated in
acute myeloid leukemia (AML) and myelodysplasia (MDS). These include transcriptional repression by
mutated or aberrantly expressed transcription factors, and aberrant epigenetic silencing by
hypermethylation of tumor suppressor or DNA repair–related genes. To target these mechanisms, several
drugs are currently under clinical trials. In this presentation, we will discuss the potential impact of this new
therapeutic approach in AML and MDS.
http://www.oncopress.net/especialistas/vespecialista.asp?id=30
10:30
Pier Giuseppe Pelicci
European Institute of Oncology; Milan, Italy
Epigenética de la leucemia promielocítica y sus fármacos / Epigenetics of acute promyelocitic leukemia and their
drugs
Molecular investigations on Acute Promyelocytic Leukemia (APL) have opened the way to modern concepts of anticancer treatment. APL has been the first example of a neoplastic disease that can be specifically treated by targeting
therapy to the transforming protein (molecular treatment) and represents a unique model for differentiation
therapy. Indeed, the APL oncogene (PML-RAR) is responsible for the high sensitivity of the blasts to the
differentiative action of retinoic acid (RA) both in vivo and in vitro. The dissection of the molecular mechanisms
underlying PML-RAR activities (chromatin recruitment of histone deacetylases, histone and DNA
methyltransferases) has demonstrated that epigenetic modifications of DNA (methylation) and chromatin
(acetylation and methylation of histones) may contribute to cancer. This has allowed the concept of epigenetic
treatment of cancer to be introduced and validated. Recent work from our lab has demonstrated that HDAC-i
induce apoptosis of leukemic blasts, that apoptosis is p53-independent and depends upon activation of the death
receptor pathway (TRAIL and Fas signalling pathway). The effects of HDAC-I treatment on RA-target genes in PMLRAR cells was negligible, thus suggesting that HDACi might target alternative mechanisms of PML-RAR activity.
Indeed, members of the TRAIL and Fas pathway are not direct RA-targets. We are currently investigating whether
PML-RAR regulates transcription of genes which do not possess RA-responsive elements (RARE). Many genes
regulated by RA and/or PML/RARa do not contain a RARE. However, these genes are clustered in long stretches of
co-regulation spanning regions up to 1 Megabase in length.These clusters are found within regions particularly
enriched with RARE consensus sequences that, surprisingly, are included within Alu repeats. Such a striking colocalization of RAR- and/or PML/RARa- regulated genes, RARE consensuses and Alu sequences suggests that the
insertion of potentially thousands of Alu repeats containing binding sites for NHRs throughout the primate genome
is likely to have played a functionally important role in the evolution of regulation of the primate gene expression.
http://www.ifom-ieo-campus.it/groups/pelicci.html
11:15
11:45
Café / Coffee
James E. Bradner
Dana–Farber Cancer Institute; Boston, USA
Inhibición selectiva de HDAC6 en la terapia oncológica /
Selective inhibition of HDAC6 in cancer therapy
Histone deacetylase enzymes represent credentialed targets for cancer therapy. Early phase clinical studies
assessing the activity of non-selective inhibitors in the treatment of hematologic malignancies have been
encouraging, though the toxic liabilities of these agents may ultimately limit their clinical development.
Consequently, targeted strategies are needed. Our recent chemical biologic exploration of this class of
enzymes has realized selective inhibition of HDAC6 and the utility of such a strategy in multiple myeloma.
Additional strategies have realized small molecule HDAC inhibitors with appealing ADME properties for
therapeutic application.
http://www.dfci.harvard.edu/pat/dana-farber/detail.asp?personID=705&group=%28Clinician%29
12:30
Roberto Pili
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Baltimore, USA
Ensayos clínicos en Fase I de inhibidores de HDAC, aislados y en combinación / Phase I trials of HDAC
inhibitors, alone and in combination
This presentation will review the HDAC inhibitors currently in clinical testing as well as, describe the rationale
for combination strategies. It will outline the clinical issues related to the drug development of this novel
class of agents.
http://www.hopkinscancer.net/experts/_doctor.cfm?action=1&doctorid=176
13:15
CONFERENCIA DE CLAUSURA / CLOSURE KEYNOTE
Joe Shih
Discovery Chemistry Research & Technology, LRL-Eli Lilly; Indianapolis, USA
El Caso de estudio del descubrimiento y desarrollo de Alimta, un nuevo antifolato multidiana para el
mesotieloma pleural maligno y el cáncer de pulmón de células no pequeña /
A Case Study of the discovery and development of Alimta, a novel multitargeted antifolate for malignanat
pleural mesothieloma and non-small cell lung cancer
ALIMTA (Pemetrexed Disodium) is a new pyrrolopyrimidne-based antifolate that was recently approved by
FDA as the first line treatment (in combination with cisplatin) for the malignant pleural mesothelioma (MPM)
and as the 2nd line treatment (single agent) for non-small cell lung carcinoma (NSCLC). ALIMTA acts through
a novel mechanism of action by inhibiting several key folate-requiring enzymes (TS, DHFR and GARFT) of the
folate metabolism. This unique multi-targeted MOA together with the vitamins (folic acid and B-12)
supplementation have made ALIMTA a highly effective and well tolerated chemotherapeutic agent. The
history of the discovery, the preclinical pharmacology and some key clinical trial results (for MPM and
NSCLC) of ALIMTA will be presented in this lecture.
14:00
Despedida y Cierre / Farewell & Closure
65


Ponencias de 30 minutos / 30-minute talks
15 minutos de discusión tras las ponencias / 15-minute discussion after each talk
SESIÓN DE PANELES: LOS AUTORES DEBEN PERMANECER JUNTO AL PANEL PARA DISCUTIR CON LOS INTERESADOS / POSTER SESSIÓN:
PRESENTING AUTHORS SHOULD STAY BY THEIR POSTER FOR DISCUSSION
Fundación Lilly
Centro Nacional de Investigaciones Oncológicas (CNIO)
LUGAR DE CELEBRACIÓN
Peter A. Jones
Carlos Caldas
Manel Esteller
Mariano Barbacid
EUROFORUM INFANTES
San Lorenzo de El Escorial, Madrid, Spain
MODERADORES y CONFERENCIANTES
Mariano Barbacid (Sp)
José-A. Gutiérrez (Sp)
Paul A Marks (USA)
Juan C Lacal (Sp)
Peter A Jones (USA)
Stephen B Baylin (USA)
Manel Esteller (Sp)
Andrew P Feinberg (USA)
Información en:
Christoph Plass (USA)
Hernán Cortés (Sp)
Robert Brown (UK)
Michael Lubbert (Ger)
Jean-Pierre J Issa (USA)
Pere Gascón (Sp)
Eugenio Santos (Sp)
Tony Kouzarides (UK)
Rob Martienssen (USA)
Tel: + 34 91 732 80 00
www.cnio.es
[email protected]
Thomas Jenuwein (Ost)
Yi Zhang (USA)
Yang Shi (USA)
Juan A Velasco (Sp)
Peter B Becker (Ger)
Genevieve Almouzni (Fr)
Maarten van Lohuizen (Neth)
Carlos Caldas (UK)
Eric Miska (UK)
Alfredo Carrato (Sp)
Francesco Lo Coco (It)
Miguel-Angel Sanz (Sp)
Pier-Giuseppe Pelicci (It)
James E Bradner (USA)
Roberto Pili (USA)
Joe Shih (USA)
Tel: +34 91 781 50 70 www.fundacionlily.com
[email protected]
Actividad Acreditada por la Comisión de Formación Continuada de las
Profesiones Sanitarias de la Comunidad de Madrid (SNS) con:
2 Créditos
La enfermedad coronaria es una de las principales causas de muerte y de consumo de recursos sanitarios en los países desarrollados. En
España, aunque su incidencia es inferior a la de otros países europeos, también representa un importante problema sanitario, ya que,
siguiendo la tendencia occidental, se sitúa como primera causa de muerte total entre los varones, y en algunas comunidades incluso
entre las mujeres.
El estudio DRECE ha puesto de manifiesto, que el perfil lipídico español no es significativamente distinto al de otras comunidades
occidentales, a excepción de una concentración de colesterol de HDL (cHDL) algo más elevada, pero que no representa en sí misma un
hecho diferencial sobre otras poblaciones como la inglesa, en que la morbi-mortalidad coronaria se estima considerablemente superior
a la española.
El seguimiento de la cohorte DRECE durante más de 15 años permite hoy empezar a aflorar resultados que muestran una particular
forma de enfermar y morir en la población estudiada, así como establecer correlaciones con los diferentes hábitos alimentarios,
factores de riesgo y parámetros bioquímicos, que van poniendo de manifiesto el perfil particular de la población española ante las
enfermedades cardiovasculares y otras prevalentes como el cáncer.
A la luz de los más recientes avances, este 10º Simposio pretende aportar a la audiencia los últimos conocimientos sobre la
importancia de la alimentación en estos procesos y como ésta puede condicionar positiva o negativamente el desarrollo de la
aterosclerosis y otras enfermedades.
Particular atención se prestará al papel que en la formación de los ateromas juegan determinadas células, lipoproteínas, antioxidantes,
o la coincidencia de diferentes patologías en el llamado Síndrome Metabólico. Sólo a través de su conocimiento y comprensión
podremos plantearnos un diagnóstico adecuado y un tratamiento consecuente y eficaz para prevenir la enfermedad.
“ALIMENTACIÓN, LÍPIDOS Y ATEROSCLEROSIS"
 Presidido por Pedro González Santos, Luis Alonso Pulpón y José A. Gutiérrez
Fuentes
"Alimentación, Lípidos y Aterosclerosis". Monográfico del 10º Simposio Científico, publicado
como Suplemento de la revista “Clínica e Investigación en Arteriosclerosis” Volumen 19,
Extraordinario 5, Noviembre 2007 (ISSN: 0214-9168)
-
Distribución: suscriptores de la revista y a los asistentes al Simposio. (3.000 ejemplares)
-
67
-PROGRAMA-
Presidencia / Chairmen
Pedro González Santos, Luis Alonso Pulpón, José A. Gutiérrez Fuentes
Lugar / Place: San Lorenzo de El Escorial, Madrid
Fecha / Date: November 17 y 18th, 2006
Viernes / Friday / 17th
08:15
08:45
Bienvenida / Welcome & Opening
09:00
Conferencia de Apertura / Keynote Address
Moderador / Chairperson: José A. Gutiérrez Fuentes. Fundación Lilly, Spain
Silvio Zaina
Institute for Medical Investigations, University of Guanajuato, Leon, Gto. México
Nutrición y epigenética en aterosclerosis /Nutrition and epigenetics in atherosclerosis
It is clear that nutrition in utero and at critical periods in childhood affects the risk of metabolic
disorders and atherosclerosis later in life. Epigenetics provides conceptual and methodological
instruments to explain these observations from a molecular point of view. The promise of
epigenetics is to indicate novel strategies for prevention and therapy of atherosclerosis and
associated risk factors.
Sesión 1/ Session 1
09:40
Nutrición, Lípidos y Aterosclerosis / Nutrition, Lipids and Atherosclerosis
Moderador / Chairperson: Pedro González Santos. Presidente Sociedad Española de
Arteriosclerosis
José María Ordovás
Nutrition and Genomics Laboratory, Tufts University, Boston, MA, USA
Dieta, obesidad y predisposición genética a la aterosclerosis / Diet, obesity and genetic
predisposition to atherosclerosis
Changes in diet are likely to reduce cardiovascular disease (CVD), but after decades of active
research and heated discussion the question still remains: what is the optimal diet to achieve this
goal? Is a low fat, as traditionally recommended by multiple medical societies? Or a high
monounsaturated fat as predicated by the Mediterranean diet? Perhaps a high polyunsaturated fat
based on the cholesterol lowering effects? The right answer may be all of the above but not for
everybody. A well-known phenomenon in nutrition research and practice is the dramatic variability
in interindividual response to any type of dietary intervention. There are many other factors
influencing response, and they include, among many others, age, sex, physical activity, alcohol,
and smoking as well as genetic factors that will help to identify vulnerable populations/individuals
that will be benefit from a variety of more personalized and mechanistic based dietary
recommendations. This potential could and needs to be developed within the context of nutritional
genomics that in conjunction with systems biology may provide the tools to achieve the holy grail
of dietary prevention and therapy of CVD. This approach will break with the traditional public
health approach of “one size fits all.”
69
10:10
Angela A. Rivellese
Department of Clinical and Experimental Medicine, Federico II University, Medical School, Naples,
Italy
Alimentación y enfermedad cardiovascular: más allá del colesterol / Diet and
cardiovascular disease: Beyond colesterol
The diet-heart hypothesis, proposed at the beginning of the last century, was essentially based on
the relationship between dietary saturated fat, serum cholesterol and coronary heart diseases. In
the last few years it has become more and more evident that this kind of hypothesis is too
reductive for many reasons. First of all atherogenesis is a complex process due to different risk
factors, not only serum cholesterol levels. Secondly, dietary components may act on all these risk
factors, thus influencing cardiovascular risk through different biological pathways. This means
that, in the identification of the optimal diet for cardiovascular disease prevention, the influence of
dietary components on all the possible cardiovascular risk factors, LDL cholesterol, but also blood
pressure, other plasma lipids, thrombotic tendency, diabetes, insulin sensitivity, postprandial
blood glucose and lipids, low-grade systemic inflammation, oxidative stress should be considered
10:40
Café / Coffee Break
11:00
Miguel A. Rubio
Departamento de Endocrinología y Nutrición, Hospital Clínico San Carlos, Madrid, Spain
Estudio DRECE: La dieta española / DRECE Study: Diet in the Spanish population
Se analiza la evolución de los hábitos alimentarios de la población española desde 1991 hasta la
actualidad a partir de los datos recogidos en los tres estudios transversales de la cohorte DRECE
(Dieta y Riesgo de Enfermedades cardiovasculares en España) en los periodos: 1991-92; 1996-97
y 2005-06. El consumo de los diferentes grupos de alimentos, el análisis de macro y
micronutrientes se mostrarán de manera descriptiva y en asociación con diferentes marcadores
de riesgo cardiovascular y mortalidad.
11:20
Juan A. Gómez Gerique
Laboratorio Análisis Clínicos, Hospital Marqués de Valdecilla, Santander, Spain
Estudio DRECE; Factores de riesgo cardiovascular en la población española / DRECE
Study: Cardiovascular risk factors in the Spanish population
El programa DRECE consiste en un estudio longitudinal que se inició en 1992 y que está
permitiendo realizar el seguimiento de cuna cohorte de 4878 incividuos en toda España. En esta
ponencia, analizaremos los principales Factores de riesgo basales y la evolución del perfil lipídico
de la población en estos 15 años de seguimiento.
11:40
Agustín Gómez de la Cámara
Unidad de Investigación - Epidemiología Clínica, Hospital 12 de Octubre, Madrid, Spain
Mortalidad en la cohorte DRECE. Incidencia y factores de riesgo / Mortality in DRECE
Cohort. Incidence and Risk Factors
4560 DRECE subjects have been followed during 12 years. Vital status and cause of death
revealed 100 exitus. Surprisingly cancer is the most frequent cause (42%) in this cohort.
Cardiovascular mortality accounts for 18 %. Diabetes mellitus appears as main risk factor for the
earliest cardiovascular death.
12:10
12:45
13:45
Discusión / Discussion General Topic 1
Seminario 1
Almuerzo / Lunch
Seminario 2
Session 2
15:15
Nuevos Avances en la Patofisiología de la Arteriosclerosis /
New Advances in Atherosclerosis Pathophysiology
Moderador / Chairperson: Rafael Carmena. Hospital Clínico, Universidad de Valencia, Spain
Michael Aviram
Lipid Research Laboratory, Rambam Medical Center, Haifa, Israel
Los antioxidantes y paraxonasas de la dieta atenúan la formación de células
espumosas y el desarrollo de la aterosclerosis / Dietary antioxidants and
paraoxonase attenuate macrophage foam cell formation and atherosclerosis
development
As macrophage foam cell formation, the hallmark of early atherogenesis, is increased under
oxidative stress and since polyphenols – rich nutrients, as well as HDL possess anti-oxidative
properties, we analyzed the effect of dietary antioxidants and that of HDL- associated
paraoxonase1 (PON1) on macrophage foam cell formation and on atherosclerosis
development. The interrelationship between pomegranate hydrolyzable tannin (punicalagin)
free radicals scavenging, and PON1 lipo-lactonase activity on oxidized phospholipids, was
shown to significantly attenuate atherosclerosis development.
15:45
Andrew D. Watson
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University
of California at Los Angeles, CA, USA
Inflamación, lipoproteínas (HDL) y aterosclerosis / Inflammation, lipoproteins
(HDL) and atherosclerosis
Oxidation of phospholipids in low-density lipoproteins (LDL) stimulates an inflammatory
response in vascular wall cells and contributes to the development of atherosclerosis. One
mechanism by which high-density lipoproteins (HDL) and HDL mimetic peptides protect
against atherogenesis is by interfering in the production and action of oxidized phospholipids
and facilitating their removal from the vessel wall and circulation.
16:15
Robin P. Choudhury
Department of Cardiovascular Medicine, University of Oxford and Wellcome Trust Clinical
Fellow and Consultant Cardiologist, UK
Células espumosas derivadas de macrófagos: Dianas clave en la aterosclerosis /
Macrophage-derived foam cells: Key target in atherosclerosis
From early fatty streak lesions to advanced plaques, macrophage-derived foam cells are
integral to the development and progression of atherosclerosis. Recent elucidation of
molecular and cellular processes involving macrophages has suggested numerous therapeutic
targets. We will consider actual and potential macrophage-directed pharmacologic
interventions; the development of drugs targeting these pathways and the emergence of
sensitive imaging techniques that have been able to identify changes in plaque size and
composition in response to treatment.
16:45
Enzo Nisoli
Center for Study and Research on Obesity, Department of Pharmacology, Chemotherapy and
Medical Toxicology, University of Milan, Italy
Fisiopatología del síndrome metabólico e implicaciones terapéuticas /
Pathophysiology of the metabolic syndrome and therapeutic implications
Metabolic syndrome is a particularly challenging clinical condition to treat because of its
complex molecular basis. Impaired cell metabolism has been suggested as a putative
pathophysiological process. Recently, we have reported that mitochondrial biogenesis and
function are increased by nitric oxide in various cell types and tissues. Moreover, we found
that endothelial nitric oxide synthase null mutant mice are affected by visceral fat
accumulation, high blood pressure, and insulin resistance with concomitant reduction of
mitochondrial content in several tissues, including adipose tissue and skeletal muscle. This
implies that a detective nitric oxide production might be linked to cell metabolism dysfunction.
Here we summarize our view on this issue and propose a novel pathophysiological hypothesis
for metabolic syndrome with putative therapeutic implications.
17:15
17:45
18:15
Seminario 1
Seminario 3
71
Sábado / Saturday 18th
Session 3
09:00
Lab-Tech y Avances Terapéuticos en las Enfermedades Cardiovasculares /
Lab-Tech & Therapy Advances in cardiovascular disease
Moderador / Chairperson: Luis Alonso Pulpón. Presidente Sociedad Española de Cardiología
Wolfgang Koenig
Department of Internal Medicine II–Cardiology, University of Ulm Medical Center, Germany
Actuales marcadores de riegos para la aterosclerosis en el laboratorio: Investigación y
aplicaciones clínicas / Atherosclerosis lab risk markers today: Research & Clinical
application
Basic research over the last two decades has identified a large number of molecules which have
clearly improved our understanding of the atherosclerotic process. Today, many of these
molecules can be measured systemically by sensitive assays, and elevated concentrations in the
circulation have been shown to carry important prognostic information, independent of traditional
risk factors, and may turn out to be useful in improving risk stratification. However, for most of
these biomarkers the clinical utility has not yet been established.
09:30
Patrick W. Serruys
Erasmus Medical Center, Thoraxcenter, Rotterdam, The Netherlands
Análisis de la composición y estabilidad de la placa / Analysis of Plaque Composition
and Stability
Rupture of vulnerable plaques is the main cause of acute coronary syndromes. Identification of
these vulnerable plaques is therefore essential to enable the development of treatment modalities
to stabilize them. Several non-invasive (MRI and MSCT) and invasive (intravascular
technologies), investigating coronary areas that will be responsible for future events, are
underlined in this presentation.
The ideal technique would provide morphological, mechanical and biochemical information;
although several imaging techniques are currently under development, none of them provides
alone such all-embracing assessment. Thus the combination of several modalities will be of
importance to ensure a high sensitivity and specificity in detecting vulnerable plaques.
10:00
10:30
Carlos Macaya
Instituto Cardiovascular, Hospital Clínico San Carlos, Madrid, Spain
Nuevos avances en cardiología intervencionista / New advances in interventional
cardiology
La implantación percutánea de prótesis valvulares y la reparación, también percutánea de la
válvula mitral son técnicas en fase de investigación preclínica y ya clínica en algunos casos. En la
enfermedad arterial coronaria, la introducción de los stents liberadores de fármacos (SLF)
antiproliferativos en la cardiología intervencionista ha relegado el problema de la reestenosis
postangioplastia a un segundo plano. Por otro lado, su uso casi generalizado de los SLFs ha
tenido impacto clínico en forma de aumentar cada vez más el número de pacientes con
enfermedad de tronco coronario izquierdo y de 3 vasos que se revascularización con
intervenciones percutáneas. No obstante se está observando un problema que afecta a la
seguridad de estos SLFs, la magnitud y prevención de la trombosis tardía de estos SLFs está por
definir y aunque el problema es infrecuente, las consecuencias clínicas son muy graves, con una
tasa de mortalidad al año superior al 50%. El desarrollo de nuevos stents con fármacos y el
desarrollo de nuevas técnicas de imagen pueden optimizar los resultados, tanto de eficacia como
de seguridad de los SLFs.
11:00
Iris Rajman
EU Exploratory Program Phase Medicine, Eli Lilly & Co., Erl Wood ELCL, UK
Desarrollo farmacológico: Utilización de marcadores biológicos en la evaluación de
eficacia / Drug Development: Use of Biomarkers in Evaluation of Efficacy
There are many challenges for clinical development of new cardiovascular medicines. Greater use
of efficacy biomarkers may provide support in both early and late clinical development.
Biomarkers of efficacy may be used as level 1, 2 or 3 biomarkers. Some of the challenges and
options for biomarker use in clinical development of new drugs to treat ‘atherosclerosis ‘ will be
discussed.
11:30
12:00
Seminar 2
Seminar 3
13:00
Conferencia Clausura / Closure Address
Moderador /Chairperson: José A. Gutiérrez Fuentes
Ira Tabas
Department of Medicine, Columbia University, New York, USA
Impacto de la resistencia insulínica sobre los condicionantes de muerte de los
macrófagos en la aterosclerosis avanzada / The Impact of Insulin Resistance on
Macrophage Death Pathways in Advanced Atherosclerosis
Macrophage death in advanced atherosclerosis causes plaque necrosis, which promotes plaque rupture
and acute atherothrombotic vascular events. Of interest, plaque necrosis and atherothrombotic disease
are markedly increased in diabetes and metabolic syndrome. We discovered a novel "multi-hit"
macrophage apoptosis pathway that appears to be highly relevant to advanced atherosclerosis. The
elements of the pathway include: (a) activation of the unfolded protein response (UPR) by cholesterol
overloading of the endoplasmic reticulum or by other UPR activators known to exist in atheromata; and
(b) combinatorial signaling involving two macrophage pattern recognition/atherogenic lipoprotein
receptors—the type A scavenger receptor (SRA) and toll-like receptor 4 (TLR4). The downstream
apoptosis effectors include CHOP (GADD153) for the UPR and JNK and STAT1 for SRA/TLR4 signaling.
Remarkably, components of this pathway are enhanced in macrophages with defective insulin
signaling, including UPR activation and SRA expression. As a result, insulin-resistant macrophages
show increased susceptibility to apoptosis when exposed to UPR activators and SRA/TLR4 ligands.
Moreover, the advanced lesions of atherosclerosis-prone mice reconstituted with insulin-resistant
macrophages show increased macrophage apoptosis and plaque necrosis. Based on these findings, we
propose that one mechanism of increased plaque necrosis and atherothrombotic vascular disease in
insulin resistant syndromes is up-regulation of a multi-hit signal transduction pathway involved in
advanced lesional macrophage death.
13:40
Seminarios: Dirigidos a la discusión y orientación de aspectos prácticos relacionados con la prevención, el diagnóstico y el
tratamiento (grupos reducidos) / Intented for the discussion and orientation of practical aspects related with the
prevention, diagnosis and treatment (limited groups)
Seminario 1
Ponente: Andreu Palou
Departamento de Biología Fundamental y Ciencias de la Salud, Universidad de las Islas Baleares,
Spain
Evaluación Científica de riesgos en materia de Seguridad Alimentaria en la Unión
Europea / Scientific Risk Evaluation For Food Security In The European Union
La evaluación de riesgos en materia de seguridad alimentaria comprende al menos las siguientes
etapas: a) identificación del problema y análisis del contexto en el que se desenvuelve; b)
caracterización del riesgo y justificación de cualquier juicio de valor o estrategia aplicada en la
evaluación del riesgo; c) elucidación de los mecanismos; d) análisis de posibles opciones aplicables en
la gestión del riesgo.
Sin embargo, la evaluación del riesgo no proporciona toda la información en la que deben basarse las
decisiones políticas o de gestión del riesgo. En todo caso, es importante que todas las partes
interesadas o afectadas por la posible decisión de gestión, hayan tenido la oportunidad de hacer sus
aportaciones al propio proceso de gestión del riesgo: organizaciones de consumidores, industrias
alimentarias, instituciones de investigación y formación, así como entidades legisladoras / reguladoras.
Las características o principios para un buen asesoramiento científico incluyen, como elementos
principales: la independencia (de toda clase de poderes e influencias) y la transparencia (con amplia
publicidad de las decisiones, incluidos los detalles y procedimientos), además de la excelencia
científica. Junto a ello es preciso que el estudio o evaluación científica se efectúe en un contexto real,
práctico, que sea efectivo, y que pueda ser comprendido (transparente) por personas no
especializadas. Probablemente la Unión Europea y los EEUU mantienen el suministro de alimentos más
seguro del planeta, y la credibilidad conseguida por los actuales paneles científicos europeos (Autoridad
Europea en Seguridad Alimentaria, European Food Safety Authority (EFSA) o instituciones como la FDA
americana (Food and Drug Administration. Administración de Drogas y Alimentos de los Estados
Unidos), no es ajena a la aplicación de los citados principios La creación de la EFSA en 2002
(http://www.efsa.eu.int/), ha supuesto la unificación en Europa de las funciones de dictamen, arbitraje
y asesoramiento científico que provisionalmente se asignaron al Comité científico de la Alimentación
Humana (SCF, Scientific Committee on Food, 1997-2002) y a otros comités en 1997, y la consolidación
de un proceso de mejora cualitativa en Europa, con una reestructuración iniciada a partir de 1996, que
no fue ajena a las crisis alimentarias. La revisión de las diferentes actividades que llevan a cabo los
diversos Paneles Científicos de la EFSA (aditivos, saborizantes y materiales en contacto, en
alimentación humana; aditivos y productos o substancias usados en alimentación animal; productos
dietéticos, nutrición y alergias; organismos modificados genéticamente; productos para la protección
vegetal; peligros biológicos; contaminantes en la cadena alimentaria; salud y bienestar animal,
residuos y salud vegetal) permite un acercamiento a como se canalizan y tratan los problemas en el día
a día de la evaluación científica de riesgos asociados a la alimentación en la Unión Europea.
73
Seminario 2
Ponente: Luis Álvarez-Sala Walter
Lipids Unit, Internal Medicine, Hospital General Universitario Gregorio Marañón, Madrid, Spain
Tratamiento farmacológico en prevención primaria / Drug treatment in primary
Prevention
Cardiovascular diseases represent the 1st cause of morbidity and mortality in Western countries.
There are several major risk factors involved in the development of these diseases. Enormous
efforts have been done to achieve several drugs able to reduce these factors, and to
demonstrate their efficacy and safety profile, not only in achieving the control of every particular
risk factor, but also reducing the incidenc e of cardiovascular events. However, as all drugs have
an economic cost and a potential incidence of adverse effects, not all the general population can
receive these drugs to prevent the disease. Several clinical guidelines and recommendations
have been developed as a tool to be applied in daily clinical practice in primary prevention of the
disease, approaching the clinical evidence to the doctor. These aspects will be discussed in a
colloquial and interactive style.
Seminario 3
Ponente: José Luis Palma Gámiz
Cardiologist, Ramon y Cajal University Hospital. Madrid.
Tratamiento farmacológico en prevención secundaria / Farmacological treatment in
secondary prevention
Cardiovascular secondary prevention plays a major role in cardiovascular morbidity and
mortality since the average age of the general population is increasing constantly and the
prevalence and risk of cardiovascular disease goes parallel. Lifestyle modification; including
smoking cessation, normalization of cholesterol plasma levels, glucose and triglycerides,
changes in eating habits and physical exercise in order to obtain a BMI < 25, is an essential
part of the general approach for secondary prevention in order to maximize the effectivity of
drug therapy. Nowadays; statins are at the central stage of the pharmacological treatment,
since a large number of trials have indicated a significant reduction of coronary events (more
than 30%). ACE inhibitors may apparently reduce the plaque formation and rupture, avoiding
the coronary vascular disaster. Also beta-blockers and aspirin (clopidogrel when aspirin is
contraindicated) can be applied for therapeutic measures. Guidelines and practical algorithms
may be an excellent help to stratify cardiovascular risk and to establish a good approach for
secondary prevention.



30 minutos de discusión al finalizar la mesa / 10-minute discussion after each session
Seminarios: En grupos reducidos, orientados a la discusión y actualización de aspectos prácticos relacionados con la
prevención, el diagnóstico y el tratamiento
Fundación Lilly
Pedro González Santos, Luis Alonso Pulpón, Agustín
Gómez de la Cámara, Miguel A. Rubio,
Juan A. Gómez Gerique, José A. Gutiérrez Fuentes
Euroforum Infantes
Luis Alonso-Pulpón Rivera (Sp)
Luis A. Álvarez-Sala Walter (Sp)
Michael Aviram (Is)
Rafael Carmena Rodríguez (Sp)
Robin P. Choudhury (UK)
Agustín Gómez de la Cámara (Sp)
Juan A. Gómez Gerique (Sp)
Pedro González Santos (Sp)
José A. Gutiérrez Fuentes (Sp)
Wolfgang Koenig (Ger)
Carlos Macaya (Sp)
Enzo Nisoli (It)
José María Ordovas (USA)
José Luis Palma Gámiz (Sp)
Andreu Palou (Sp)
Iris Rajman (UK)
Angela A. Riveselle (It)
Miguel Angel Rubio (Sp)
Patrick W. Serruys (NL)
Ira Tabas (USA)
Andrew D. Watson (USA)
Silvio Zaina (Mx)
Información en:
Tel: +34 91 781 50 70 – 71 www.fundacionlily.com ; [email protected]
ENGLISH <> SPANISH : TRADUCCIÓN SIMULTANEA <> SIMULTANEOUS TRANSLATION PROVIDED
Las enfermedades del sistema nervioso ocasionan más del 20% del gasto sanitario en los países desarrollados, y es muy
posible que esta proporción aumente en el futuro. Según los cálculos de la Organización Mundial de la Salud sobre la
carga que suponen las enfermedades medida en DALY’s, el 9% corresponde a las enfermedades mentales, el 1,7% a las
enfermedades cerebrovasculares, y el 34% a problemas del comportamiento. En total, puede decirse que alrededor del
45% de la carga de las enfermedades corresponde al comportamiento o al órgano que lo regula. Además, entre las 10
enfermedades con mayor carga, 5 son trastornos mentales.
De estos hechos, solo cabe deducir que las enfermedades del sistema nervioso son un reto sanitario de primera
magnitud y que la investigación en el ámbito de la neurociencia tiene ante sí la gran tarea de conseguir aumentar los
conocimientos necesarios para hacer frente a estas enfermedades.
Al mismo tiempo, la neurociencia tiene otro reto, al menos tan importante como aquel, que es el de conocer el
funcionamiento del sistema nervioso, en todo lo relacionado con nuestra actividad psíquica y con lo que nos caracteriza
como seres humanos conscientes, tanto a nivel individual como al nivel de especie. En ella, la combinación de
perspectivas clínicas y básicas ha demostrado ser un camino fructífero y apasionante. Por vez primera, empezamos a
atisbar la posibilidad de conocer lo que durante siglos han sido los sueños de filósofos y pensadores y, en el fondo, la
inquietud de cualquier ser humano.
investigación del sistema nervioso puede dar ante el reto de enfermedades tan discapacitantes y frecuentes como la
depresión y el síndrome bipolar, algunas de las cuales han sido causa de temores y estigmas muy extendidos a lo largo
de los siglos, y que han tenido su origen en la ignorancia y los prejuicios.
“NEUROCIENCIA: DEPRESIÓN Y TRASTORNO BIPOLAR"
 Presidido por Juan José López-Ibor, Julio Vallejo y Steven Paul
"Neurociencia: depresión y trastorno bipolar". Monográfico de las ponencias del 11º Simposio
Científico, publicado como Suplemento de "Actas de Psiquiatría”. Volumen 36, Suplemento 1,
Enero 2008 (ISSN: 1139-9287)
-
Distribución: suscriptores de la revista Actas ESpapañolas de Psiquiatría y a los asistentes al
-
Grabación del Simposio accesible en la página web (www.fundacionlilly.com)
75
-PROGRAMA-
Presidencia / Chairmen
Juan José López-Ibor ▫ Julio Vallejo ▫ Steven Paul
Lugar / Place: Auditorio San Carlos, Hospital Clínico, Madrid
th
th
Fecha / Date: April 11 & 12 , 2007
th
Miércoles / Wednesday / 11
08:15
08:30
Conferencia inaugural / Keynote Address
Moderador / Chairperson: Juan José López-Ibor. Professor and Head, Service of Psychiatry, Hospital Clínico San Carlos, Madrid, Sp
08:45
Husseini Manji
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, NIMH, Bethesda, MD, USA
Cascadas de la plasticidad neuronal: desde los genes a la conducta en la patofisiología y el tratamiento del
trastorno bipolar / Cellular Plasticity Cascades: Genes to Behavior Pathways in the Pathophysiology and
Treatment of Bipolar Disorder
+ info
Session1
09:30
The “molecular medicine revolution” has brought to bear the power of sophisticated cellular and molecular biologic
methodologies to tackle many of society’s most devastating illnesses. This has allowed the study of a variety of
human diseases which are caused by abnormalities in cell to cell communication; studies of such diseases are
offering unique insights into the physiologic and pathophysiologic functioning of many cellular signaling pathways. It
is clear that bipolar disorder is a disorder of “synapses and circuits,” not “too much/too little” of individual
neurotransmitter systems. A major defect is in the ability to regulate neuroplastic adaptations to perturbations
(both physiological and pathophysiological) without failing or invoking compensatory adaptations that overshoot and
predispose to oscillations. Many of the very same “plasticity regulators” also play a critical role in cell survival, cell
atrophy, and cellular resilience. New genomics and proteomics technologies are also being utilized to facilitate the
identification of genes that are regulated by mood stabilizers, and have led to novel and completely unexpected
targets, most notably neurotrophic signaling cascades. Optimal long term treatment for these devastating disorders
may only be attained by providing both trophic and neurochemical support; the trophic support would be envisioned
as enhancing and maintaining normal synaptic connectivity, thereby allowing the chemical signal to reinstate the
optimal functioning of critical circuits necessary for normal affective functioning. There are a number of
pharmacologic “plasticity enhancing” strategies being investigated which may be of considerable utility in the
treatment of mood disorders; this research hold much promise for the development of novel therapeutics for the
treatment of Bipolar Disorder.
DEPRESIÓN: ACTUALES RETOS SANITARIOS Y CLÍNICOS / DEPRESSION SANITARY & CLINICAL CHALLENGES TODAY
Moderador / Chairperson: Juan José López-Ibor
Enric Álvarez
Service of Psychiatry, Hospital Universitario Sant Pau, Barcelona, Sp
Límites de la depression / Depression limits
La vulgarización del término depresión ha conllevado a una borrosidad del término que parece haberse extendido a
los médicos no especialistas en Psiquiatría. Por otra parte la respuesta terapéutica a los síntomas depresivos
inducidos por situaciones adaptativas al tratamiento con los modernos fármacos antidepresivos es percibido por los
médicos de familia y lamentado, injustificadamente, por algunos responsables de la gestión de la salud pública.
La situación contrasta con la claridad y estabilidad diagnóstica de la depresión desde el punto de vista de la
Psiquiatría en relación a los síntomas depresivos reactivos, el temperamento depresivo o simplemente la tristeza
como emoción básica.
En esta presentación se intentará clarificar la situación y relacionar las distintas situaciones comentadas sin
detrimento de mantener la necesidad de un diagnostico claro y estable para las enfermedades depresivas. La
metodología utilizada es la consideración de la depresión según el modelo médico, sus bases bioquímicas y la
acción de los fármacos antidepresivos.
77
10:00
Michael Thase. Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Remisión de la depresión: ¿una meta alcanzable? / Depression remission: a possible outcome?
The conventional definitions of a favorable outcome in a randomized clinical trial of an antidepressant
medication were established in the 1960s and 1970s. Typically, patients were considered to have responded
when there was at least a 50% decline in a standardized depression score after four to six weeks of therapy.
Alternatively, the treating clinician's global judgment that there had been “much” or “very much” improvement
was sometimes utilized. Although response so defined is a valid indicator of therapeutic benefit, it was never
intended to represent an optimal therapeutic outcome. There is, for example, ample evidence that patients who
have responded, but who continue to manifest residual depressive symptoms, have persistent psychosocial
impairments and a greater risk of relapse. It is also possible for patients with very severe depressive episodes to
improve sufficiently enough to be declared responders, yet still meet syndromal criteria for a major depressive
episode. As a result of these limitations, there has been growing interest in the use of a more complete level of
improvement, for example, remission of the depressive episode as the primary indicator of antidepressant
efficacy. This presentation will review the evidence from both naturalistic and controlled studies that supports
the validity of the remission definition.
10:30
Patrik Sobocki. Center for Health Economics, Stockholm School of Economics, Stockholm, Sweden
Repercusión de los trastornos afectivos sobre los costos de la Salud Pública / Affective disorders impact on
Public Health cost in Europe
Depression is a major concern for the European health systems, employers and families. The economic burden of
depression has been estimated at €120 billion per year, exceeding those of all other disorders in CNS. Research
investments into affective disorders only make up a couple of percentage of the societal cost of the disease. This
demands new efforts at a European level, in order to save the minds of Europe
11:00
DEPRESIÓN: DESAFÍOS BIOLÓGICOS ACTUALES / DEPRESSION BIOLOGICAL CHALLENGES TODAY
Moderador / Chairman: Julio Vallejo. Service of Psychiatry, Hospital de Bellvitge, Barcelona, Sp
11:30
Klaus Peter Lesch. Molecular and Clinical Psychobiology, Department of Psychiatry and Psychotherapy, University
of Wurzburg, Germany
Factores genéticos y ambientales en la configuración de los diferentes comportamientos / Genetic and
environmental factors in the configuration of behavioral differences
(+info)
Although research on the neurobiology of behavioral differences, such as emotionality, is still in its infancy,
several milestones have already been reached: Variation in gene expression were confirmed to play a
predominant role in individual differences in emotionality; gene x environment interaction were established in
humans as well as the nonhuman primate and rodent model; gene-phenotype correlations were substantiated by
functional neuroimaging; as well as the notion that both genes and environmental factor impact on brain
development and thus set the stage for emotion regulation is increasingly appreciated. Investigation of subtle
alterations in the expression of genes of the serotonergic pathway, such as the serotonin transporter (5HTT), of
correlations between 5HTT genotype and brain activity, and of environmental variables interacting with 5HTT
variants currently strengthen research on the genetics and epigenetics of emotionality.
12:00
Svenn Torgersen, Psychology Institute, University of Oslo, Norway
+info
Epidemiología genética de la depresión mayor / Genetic epidemiology of major depression
Major depression runs in families. The familial transmission is (almost exclusively) genetic. Close to half the cause
of the development of major depression is explained by heredity. A higher genetic liability seems to result from
twin studies of clinical samples compared to common population samples. Major depression seems to be
genetically related to anxiety disorder (especially generalized anxiety disorder) on the one side, and bipolar
disorders on the other side. Genetic factors may have a direct effect on the experience of depressive affects and
thoughts. However, they may also act through personality traits, causing negative events that it its turn release
clinical depression.
Francisco Artigas
Department of Neurochemistry, Institut d'Investigacions Biomèdiques de Barcelona (IIBB) -CSIC – IDIBAPS,
Barcelona, Sp
12:30
Estrategias para mejorar la acción de los antidepresivos: enfoque sobre los receptores 5-HT / Strategies to
improve antidepressant action: focus on 5-HT receptors
Selective Serotonin Reuptake Inhibitors (SSRIs) are the most widely used antidepressant drugs (AD), due to their
excellent safety and tolerability. However, as with other AD, they have a limited efficacy and slow onset of clinical
action. Preclinical research has identified a number of cellular mechanisms potentially responsible for the
suboptimal therapeutic action of SSRIs. The talk will review the role of several 5-HT receptors (5-HT1A, 5-HT1B, 5-HT2A,
5-HT2C and 5-HT3) as potential therapeutic targets to accelerate or enhance the clinical action of SSRIs.
www.iibb.csic.es
13:00
Seminario 1
Seminario 2
14:00
Almuerzo / Lunch
DEPRESIÓN: RETOS ACTUALES DEL TRATAMIENTO / DEPRESSION TREATMENT CHALLENGES TODAY
Moderador / Chairman: Jesús Ávila. Centro de Biología Molecular "Severo Ochoa", CSIC, Madrid, Sp
15:30
Brian E Leonard
Pharmacology Department, National University of Ireland, Galway, Ireland
Actuales medicamentos antidepresivos / Current antidepressant drugs
For over 50 years, antidepressants have been developed based on the assumption that the primary disorder in
depression is related to a dysfunctional noradrenergic and/or serotonergic system. This has resulted in a plethora of
modestly effective drugs that are presumed to enhance the activity of these biogenic amines. However, a substantial
minority of depressed patients show inadequate response to treatment. As there is now evidence that effective
treatment is associated with repair of damaged neuronal networks, perhaps it is timely to consider how improvements
may be made to existing, and future, antidepressants.
16:00
Sidney H. Kennedy
Bipolar Guidelines Group, Canadian Network for Mood and Anxiety Treatments, Department of Psychiatry, University
of Toronto, Can
Tratamientos alternativos en la depresión refractaria / Refractary depression alternative treatments
Results from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) series of studies indicate that
even after 4 consecutive trials under “real world” conditions, approximately 50% of patients have not achieved
remission. These findings support the need to differentiate sub-populations, whether on the basis of symptomatology,
neurobiology or other variables to deliver optimally matched treatments.
This presentation will focus on Deep Brain Stimulation (DBS) to cingulate area 25 as a hypothesis driven investigational
procedure for Treatment Resistant Depression (TRD). Comparison of outcomes between DBS and other
neuromodulation therapies including Transcranial Magnetic Stimulation and Vagus Nerve Stimulation will also be
addressed.
16:30
Gerard Marek
Neuroscience Discovery Research, LRL, Lilly Corporate Center, Indianapolis, USA
Eficacia antipsicótica de los agonistas del receptor mGlu2/3 / Antipsychotic efficacy of mGlu2/3 receptor agonists
All currently used antipsychotic drugs used in schizophrenia block dopamine receptors. Based on preclinical models
(PCP-induced hyperactivity,CAR), mGlu2/3 receptor agonists have been suggested as potential antipsychotic drugs. A
recent phase II study assessed the therapeutic potential of a prodrug for a mGlu2/3 agonist schizophrenic patients.
This mGlu receptor agonist prodrug significantly improved both the negative and positive symptoms of schizophrenic
patients. This work builds upon the previous demonstration for anxiolytic effects of mGlu2/3 receptor agonists.
17:00
17:30
Café / Coffee
Seminario 1
Seminario 3
th
Jueves / Thursday 12
Session 2
09:00
EL TRASTORNO BIPOLAR COMO DESAFÍO / BIPOLAR DISORDER AS A CHALLENGE
Moderador / Chairman: Eduard Vieta. Institut d'Investigacions Biomediques Agustí Pi Sunyer. Service of Psychiatry, Hospital
Clínico de Barcelona, Sp
Frederick K. Goodwin
Center on Neuroscience, Medical Progress and Society, George Washington University Medical Center, Department of
Psychiatry, Washington, DC, USA
Historia del trastorno bipolar / History of bipolar disorder
Kraepelin’s concept and descriptions of manic-depressive illness encompassed all major recurrent mood disorders.
Subsequent investigators, principally Leonhard, Perris, Angst and Winokur subdivided manic-depressive illness into unipolar
and bipolar based on the presence or absence of a prior history of mania. The NIMH group (Dunner, Gershon and Goodwin)
subsequently subdivided the bipolar group into BP I and BP II based, respectively, on a history of mania vs. hypomania only.
Like Kraepelin, the original UP –BP distinction was based on studies of patients with recurrent affective disorders.
Notwithstanding this history, the architects of DSM III and IV separated out bipolar disorder “from the top,” implicitly making
polarity the primary basis for organizing the mood disorders, relegating recurrent depression to a tertiary subcategory of
depressive disorders. Furthermore the recurrent depression category is so broad that it includes patients with as few as two
episodes in their lifetime.
www.drgoodwin.com I will propose that this fundamental shift in the evolution of the DSM system has de-emphasized the importance of
recurrence, and by so doing, has contributed to the underdiagnosis of bipolar disorder as well as posing problems for
biological, pharmacological, and genetic research.
79
Gregor Hasler
Mood and Anxiety Disorders Program, NIH, National Institute of Mental Health, Bethesda, USA. Department of
Psychiatry, University Hospital, Zurich, Switzerland
09:30
Endofenotipos neurobiológicos del trastorno bipolar / Neurobiological endophenotypes for bipolar disorder
Research aimed at elucidating the underlying neurobiology and genetics of Bipolar Disorder, and factors
associated with treatment response have been limited by a heterogeneous clinical phenotype. Findings of altered
brain function and structure, and response to pharmacological challenge in bipolar patients and their relatives
will be presented and discussed with respect to their potential use as endophenotypes in genetic and clinical
studies.
Michael Bauer
Department of Psychiatry and Psychotherapy, Universitätsklinikum Carl Gustav Carus, Dresden, De
10:00
Diferencias entre trastorno bipolar y esquizofrenia en las fases tempranas de la enfermedad / Differences
between bipolar disorder and schizophrenia in the early phases of the illness
In the last decade, research on characteristics of prodromal and early phases of psychotic disorders demonstrated
the importance for early recognition of severe psychiatric diseases. Currently, research focuses on the early
symptomatology of bipolar disorders which could provide the chance for timely and adequate intervention and
therefore prevention of adverse long-term outcomes. Patients experiencing the early phase of bipolar disorders
present with specific symptoms but also have many characteristics in common with subjects developing other
types of psychiatric illnesses, including schizophrenia. An overview of the overlapping and differentiating features
in the early phases of bipolar disorder and schizophrenia will be given.
10:30
TRASTORNO BIPOLAR: RETOS PARA LA INVESTIGACIÓN / BIPOLAR DISORDER: RESEARCH CHALLENGES
Moderador / Chairman: Mauricio Tohen. Harvard Medical School, Boston, MA. Distinguished Lilly Scholar, LRL, Lilly Corporate Center,
Indianapolis, USA
Peter McGuffin
Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's
College, London, UK
11:00
Genética de los trastornos bipolares / Genetics of Bipolar Disorder
There is strong evidence from family and twin studies, supported by some adoption data of an important
genetic contribution to bipolar disorder. The mode of transmission is complex and almost certainly involves
multiple genes of small effect, even though the overall heritability is high at around 80%. Recent twin analysis
suggests overlapping effects with both unipolar depression and schizophrenia. Recent molecular studies
confirm the overlap with schizophrenia involving at least two different chromosomal regions and a number of
positional candidate genes. Results are also beginning to emerge from a very large scale whole genome
association study suggesting new susceptibility loci that were previously undetected by linkage or candidate
gene approaches.
Kiki Chang
Stanford University, School of Medicine, Department of Psychiatry and Behavioral Sciences, Division of Child
Psychiatry and Child Development, California, USA
11:30
Anomalías cerebrales previas al desarrollo del trastorno bipolar / Brain abnormalities prior to the
development of bipolar disorder
Studying populations at high-risk for developing bipolar disorder allows for identification of characteristics that
may present risk factors (bipolar traits or endophenotypes) for bipolar development. This presentation will
review brain imaging findings in patients already with bipolar disorder and discuss the emerging literature in
morphometric, spectroscopic, and functional imaging findings in at-risk populations. These findings point to
abnormalities in prefrontal-subcortical circuits that may underlie the pathophysiology of bipolar disorder.
+Info
Mary L. Phillips
Department of Psychiatry, University of Pittsburgh, PA, USA
12:00
Anomalías cerebrales que distinguen el trastorno bipolar de la depresión unipolar / Brain abnormalities that
distinguish bipolar disorder from unipolar depression
My research has focused on examination of specific functional abnormalities in neural systems underlying
emotion processing and emotion regulation that may be present as biomarkers of disorder in individuals with
major psychiatric disorders, including bipolar disorder and unipolar depression. The identification of these
biomarkers is, I believe, a crucially important step toward the long-term goal of improving diagnostic accuracy
in individuals presenting in the early stages of psychiatric illness. I have also begun to focus on examination of
the extent to which markers of dysfunction in neural systems underlying emotion processing may act as
predictors of response to specific treatments in individuals suffering from affective disorders, and may be
present in individuals at high genetic risk of future development of these disorders.
(+info)
12:30
13:30
Seminar 2
Seminar 3
Almuerzo / Lunch
LA ENFERMEDAD BIPOLAR: DIFERENTES CARAS DE UN TRASTORNO / BIPOLAR DISEASE: DIFFERENT FACES FOR A DISORDER
Moderadora / Chairwoman: Ana González Pinto. Department of Psychiatry, Santiago Apostol Hospital, Osakidetza Mental Health System,
Vitoria, Sp
Eduard Vieta
Department of Psychiatry, Institute of Neuroscience, Hospital Clinic, Barcelona, Sp.
15:00
Funcionamiento cognitivo en el trastorno bipolar / Cognitive functioning in bipolar disorder
Cognitive dysfunctions and their neurochemical correlates play a central role in the pathophysiology of bipolar disorder.
Bipolar patients show subtle but clinically relevant neuropsychological disturbances, which go beyond acute episodes
and have a significant impact on treatment outcome. Changes in brain neuroplasticity may correlate with the cognitive
findings and the behavioral effects of pharmacotherapy (1-2).
1: Tabares-Seisdedos R, Escamez T, Martinez-Gimenez JA, Balanza V, Salazar J, Selva G, Rubio C, Vieta E, Geijo-Barrientos
E, Martinez-Aran A, Reiner O, Martinez S. Variations in genes regulating neuronal migration predict reduced prefrontal
cognition in schizophrenia and bipolar subjects from mediterranean Spain: a preliminary study. Neuroscience.
2006;139(4):1289-300.
www.idibaps.ub.ed 2: Martinez-Aran A, Vieta E, Reinares M, Colom F, Torrent C, Sanchez-Moreno J, Benabarre A, Goikolea JM, Comes M,
u
Salamero M. Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. Am J
Psychiatry. 2004 Feb;161(2):262-70.
Mauricio Tohen
Distinguished Lilly Scholar for Neurosciences Lilly Research Laboratories, Eli Lilly Company, Indianapolis, USA
15:30
Episodio bipolar y episodio índice / Bipolar episode and index episode
Type of index episode in bipolar disorder may have implications in terms of outcome and response to treatment.
Furthermore efficacy of relapse prevention may be pole-specific. Naturalistic studies and clinical trial information
addressing these topics will be reviewed
Ralph W. Kupka
Altrecht Institute for Mental Health Care, Utrecht, Netherlands
16:00
Ciclado rápido, hipomanía mixta y pronóstico / Rapid cycling, mixed hypomania and prognosis
Bipolar disorder is commonly associated with distinct episodes of euphoric mania and melancholic depression. However,
in many patients, admixtures of manic and depressive symptoms are the rule rather than the exception, and may
complicated both adequate diagnosis and treatment. Rapid cycling is prevalent in about 20% of patients and has a less
favorable response to pharmacologic treatment. In this presentation, characteristics of mixed states and rapid cycling will
be discussed, as well as pharmacological treatment options and strategies.
Conferencia de clausura / Closure Conference
Moderador / Chairman: Mauricio Tohen
16:30
Mario Maj
Department of Psychiatry, University of Naples SUN, Italy
La ‘folie circulaire’ de Falret como variación del trastorno bipolar: antiguas y recientes evidencias / Falret’s ‘folie
circulaire’ as a distinct variety of bipolar disorder: old and new evidence
The origin of the concept of bipolar disorder is commonly traced back to the mid-1800 contributions by Falret on
“la folie circulaire” (“circular insanity”) (1) and Baillarger on “la folie à double forme” (“dual form insanity”) (2). The
continuity between these contributions and Kraepelin’s description of manic-depressive insanity is correctly
pointed out. One aspect, however, is usually overlooked: both Falret and Baillarger, contrary to Kraepelin,
described a specific variety of bipolar disorder: the one characterized by the direct, regular transition from mania
to depression or vice versa. Both of them regarded this “circular” form as distinct from those cases in which manic
and depressive episodes occur separately and both considered this distinction as significant. Falret reported that
“circular insanity is very hereditary” and “infinitely more frequent in females than in males”, and stated that
“mania and melancholia, when they occur in isolation, are more treatable than when they occur together in
circular insanity”. Modern generations of psychiatrists have not ignored Falret and Baillarger’s teaching
completely. In fact, some scholars of manic-depressive illness have explicitly distinguished a “circular” form of the
disease, having a poor prognosis (e.g., 3), while others have reported that the tendency to switch is a predictor of a
worse outcome (e.g., 4-6). Turvey et al. (7) reported that “polyphasic episodes” (i.e., episodes including at least
two switches in polarity) are associated with a poor prognosis, concluding that “it is more likely that patients who
switch have a more severe form of bipolar disorder which manifests as affective instability”. We found that a
polyphasic index episode, especially if starting with depression, was associated with a poor outcome in bipolar
disorder (8). Thus, currently available research provides some evidence that Falret and Baillarger were actually
right: i.e., that the regular switch from one polarity of mood to the other may identify a variety of bipolar disorder
with a characteristic prognosis, treatment response and perhaps pathophysiology. This pattern may represent a
significant target for new pharmacological and psychosocial treatment strategies.
17:30
Despedida y Clausura / Farewel & Closure
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Seminarios:
Dirigidos a la discusión y orientación de aspectos prácticos relacionados con la prevención, el diagnóstico y el tratamiento (grupos reducidos)
/ Intented for the discussion and orientation of practical aspects related with the prevention, diagnosis and treatment (limited groups)
Ponente: César Soutullo. Depart. of Psychiatry and Medical Psychology, Clínica Universitaria de Navarra,
Pamplona, Sp
Miércoles 11, 13:00 h y Miércoles 11, 17:30 h
Seminario 1
TRASTORNO BIPOLAR EN NIÑOS Y ADOLESCENTES / BIPOLAR DISORDER IN CHILDREN AND ADOLESCENTS
Bipolar disorder (BD) is a chronic, highly genetic psychiatric disorder, that usually begins in adolescence or early
adulthood associated with significant morbidity and mortality, with similar gender and cross-cultural
prevalence. Pepubertal-onset BD frequently has a phenotype that includes non-episodic, chronic, rapid-cycling,
mixed manic state, that may be comorbid with attention-deficit hyperactivity disorder (ADHD), and Conduct
Disorder (CD), or have features of ADHD and/ or CD as initial manifestations. In this seminar we will review data
on the phenomenology, clinical course, and treatment of pediatric BP that will help participants to better
identify this condition in children & adolescents.
www.cun
Ponente: Jerónimo Sáiz. Service of Psychiatry, Hospital Universitario Ramón y Cajal, Madrid, Sp
Miércoles 11, 13:00 h y Jueves 12, 12:30 h
Seminario 2
DEPRESIÓN REFRACTARIA / REFRACTIVE DEPRESSION
Despite refinements to the existing therapeutic modalities, there remains a significant subpopulation of
severely ill patients with refractory mood disorders who fail to achieve a clinical response. The therapeutic
approach to these cases has relied on pharmacotherapy in various sequences and combinations,
electroconvulsive therapy and other stimulation techniques. This presentation reviews the evidences, benefits
and risks of all known therapies.
Ponente: Francesc Colom. Service of Psychiatry, Hospital Clínico de Barcelona, Barcelona, Sp
Miércoles 11, 17:30 h y Jueves 12, 12:30 h
Seminario 3
LA PSICO-EDUCACIÓN COMO FACTOR PRNÓSTICO EN EL TRASTORNO BIPOLAR / PSYCHO-EDUCATION AS
PROGNOSIS FACTOR IN BIPOLAR DISORDER
Group psychoeducation has shown its efficacy on prevention of all sort of bipolar recurrences, including
mania/hypomania, mixed episodes and depression. At the conclusion of this workshop the participant should
be able to acknowledge the impact of psychoeducation in the prophylaxis of recurrences in bipolar disorder,
with special emphasis on long-term outcome.

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10 minutos de discusión después de cada ponencia / 10-minute discussion after each talk
Seminarios: Duración, 1 hora: Exposición, 20 min; Coloquio con los asistentes, 40 min. Grupos reducidos
Fundación Lilly
Juan José López-Ibor
Julio Vallejo
Inmaculada Gilaberte
Yolanda Martín
Juan José López-Ibor, Sp
Julio Vallejo, Sp
Steven Paul, USA
Husseini Manji, USA
Patrik Sobocki, Sweden
Enric Álvarez, Sp
Michael Thase, USA
Julio Vallejo, Sp
Klaus Peter Lesch, Ger
Svenn Torgersen, Nor
Francisco Artigas Sp
Jesús Ávila, Sp
Brian E Leonard, Ireland
Sidney H. Kennedy, Can
Gerard Marek, USA
Eduard Vieta, Sp
Frederick K. Goodwin, USA
Gregor Hasler, Switzerland
Michael Bauer, Ger
Mauricio Tohen, USA
Peter McGuffin, UK
Kiki Chang, USA
Mary L. Phillips, USA
Ana González Pinto, Sp
Ralph W. Kupka, Net
Mario Maj, It
César Soutullo, Sp
Jerónimo Sáiz, Sp
Francesc Colom, Sp
José A. Gutiérrez Fuentes, Sp
Información en: Tel: +34 91 781 50 70 – 71 www.fundacionlily.com ; [email protected]
El conocimiento y análisis de los cambios en la diversidad y la WIRING STRUCTURE de los sistemas microbianos
asociada con determinados ambientes, deberían suponer herramientas exquisitamente sensibles para la detección de
alteraciones ecológicas. Pero por desgracia, los microbios no son visibles al ojo humano, y resultan escasamente atractivos para
los seguidores de programas de TV como los de National Geographic, con lo que la propensión natural es a no tener en cuenta
los daños ocasionados por los humanos a las comunidades de microbios, estos pequeños nativos amazónicos. Sin embargo, si
cualquier tipo de vida es posible en la Tierra, es debido a que los sistemas microbianos están ahí, asegurando pasos críticos en
los ciclos del nitrógeno, el oxígeno o el carbono. Una cuestión básica es si actualmente somos capaces, o no, de definir la
diversidad microbiana. Este año conmemoramos el 300 aniversario de Carolus Linneus, la persona que más contribuyó a la
clasificación –y en consecuencia en la posibilidad de medir la diversidad- de los organismos vivos. Pero esta conmemoración no
debe descartar la denuncia de la estupidez histórica que supuso clasificar las bacterias como si fuesen plantas, un error tozudo
que ha sido responsable de una infravaloración de varios órdenes de magnitud de la verdadera diversidad microbiana.
Precisamos métodos mejores y altamente estandarizados para llegar a entender la diversidad microbiana,
incluyendo la diversidad y complejidad de los sistemas microbianos. Los cambios en esta diversidad –ya sea aumentándola o
disminuyéndola- pueden servir como sensores de las perturbaciones ecológicas. Necesitamos estos datos para construir
modelos integrados sobre como los procesos sociales, industriales o tecnológicos podrían afectar la ecología microbiana y las
consecuencias de ello sobre la sostenibilidad de la vida humana en la Tierra. De hecho, las enfermedades infecciosas son
enfermedades ecológicas, altamente dependientes de los cambios ambientales. Con demasiada frecuencia la medicina ha
ignorado la ecología, focalizando su atención en los campos más próximos de la etiología, la patogénesis, o la epidemiología.
Este Simposio intenta modificar esta visión, enfatizando la responsabilidad de los microbiólogos clínicos, especialistas en
enfermedades infecciosas, responsables de salud pública, y políticos en conseguir incrementar el interés y los recursos puestos
al servicio del mayor conocimiento sobre las causas y las consecuencias de dañar los sistemas microbianos en la Tierra,
prediciendo y corrigiendo a su debido tiempo posibles situaciones catastróficas.
Es objetivo del 12º Simposio Científico de la Fundación Lilly colaborar a introducir el pensamiento evolucionista en los
microbiólogos clínicos, los especialistas en enfermedades infecciosas y todos los profesionales relacionados con la salud pública.
Los participantes encontrarán diferentes ejemplos de cómo la evolución actúa sobre los microbios y los humanos, y como ello
influye sobre las enfermedades infecciosas. Deseamos que estos ejemplos colaboren a introducir una orientación evolutiva en la
diaria interpretación de los hechos observados, ya en el laboratorio, ya junto a la cama del paciente.
“CAMBIOS AMBIENTALES, SISTEMAS MICROBIANOS E INFECCIONES”
 Presidido por Fernando Baquero, César Nombela y Gail Cassell.
 Celebrado en el Auditorio de San Lorenzo de El Escorial de Madrid.
"Environmental changes, microbial systems and infections” Resúmenes de las ponencias del
12º Simposio Científico. Clinical Microbiology and Infection. Jan 2009; vol.15, Suppl.1
-
Distribución: suscriptores de la revista CMI, órgano de la Sociedad Europea de
Microbiología.y a los asistentes al Simposio. (1.000 ejemplares)
83
-PROGRAMA-
Directores / Chairmen: Fernando Baquero, César Nombela, Gail Cassell
Lugar / Place: EUROFORUM INFANTES, San Lorenzo de El Escorial, Madrid
Fecha / Date: November 15th & 16th, 2007
JUEVES/ Thursday / 15th
08:00
08:30
08:45
Conferencia inaugural / Opening lecture
Julian Davies, Vancouver, Canada
Todo depende de todo lo demás / Everything depends on everything else
My title is a tenet of a NW Canadian Indian Band and it refers to interactions
between Humans and Nature. Recently, this concept has been recognized in
biology. Everything down to gene sequence is a part of complex biochemical
networks; nothing is an independent entity. The knowledge that all biological
molecules and cells are contingent and act in a context specific manner is changing
traditional concepts of drug screening (single targets) and can be expected to lead
to new classes of antibiotics and other drugs.
SESIÓN 1 / SESSION 1
CAMBIOS AMBIENTALES Y TRAYECTORIAS EVOLUTIVAS MICROBIANAS / ENVIRONMENTAL CHANGES
AND MICROBIAL EVOLUTIONARY TRAJECTORIES
Moderador / Chairperson: Fernando Baquero, Madrid, Spain
09:30
Fernando Baquero, Madrid, Spain
Estrés ambiental y desarrollo evolutivo en los sistemas microbianos /
Environmental stress and evolution in microbial systems
The robustness of bacterial metabolism, cells, or systems, generally tolerates small
(or predictable) fluctuations in the environment. When fluctuations go beyond a
certain limit of tolerance, stress occurs and only genetic variability offers new
adaptive ways to natural selection. Most genetic changes occur by mutation and
recombination (internal recombination or horizontal acquisition of foreign
sequences). As any change has a de-stabilizing risk, genetic change should be
managed by novel changes and re-adaptations. Because of that, environmental
changes are major driving forces for bacterial evolution.
10:00
Andrés Moya, Valencia, Spain
Cambios ambientales y transición de organismos de vida libre a organismos
de vida intracelular / Environmental change driving transition from freeliving to intracellular pathogens
Genomics has unveiled common molecular aspects regarding the establishment and
maintenance of symbiotic associations. Several scenarios allowed the evolution of
symbiotic associations, from the first stages of free-living bacteria, through
facultative symbiosis, towards the stage of obligate endosymbiosis. The process
begins with host invasion, using the same molecular machinery used by pathogens,
and ends in huge genetic and phenotypic changes. Comparative analyses of reduced
symbiotic genomes are of relevance on fields like Systems and Synthetic Biology.
85
10:30
José-Luis Martínez, Madrid, Spain
Hacia una aproximación ecológica a los antibióticos y los genes de
resistencia antibiótica / Towards an ecological approach to antibiotics and
antibiotic-resistance genes
Antibiotics have been searched on purpose as bacterial killers. Since a large number
of antibiotics have are produced by environmental organisms, it was though that the
actual function of these molecules in Nature should be the Darwinian fighting against
competitors. Conversely, antibiotic resistance genes should be shields to avoid
antibiotic weapons action. We will discuss in this presentation that antibiotics may
act as signaling molecules in Nature and that antibiotic resistance genes may have a
relevant role in the basic bacterial metabolism. This view provides a new
interpretation on the ecological role of antibiotics and antibiotic resistance genes in
Nature.
11:00
11:30
César Nombela, Madrid, Spain
Detección de estrés medioambiental en organismos fúngicos / Fungi
sensing environmental stresses
MAP kinase signalling pathways control virulence factors of pathogenic fungi such as
the generation of a stable protection by the cell wall, morphogenesis to invade host
tissues and resistance to oxidative stress. The functionality of these pathways
represents a key element for adaptation to environmental stress. Therefore, MAP
kinases are central to a network of pathways that integrate, amplify and modulate
protective and adaptive responses.
12:00
12:30
13:30
SESIÓN 2
15:30
Discusión / Discussions General Topics 1
Seminario 1
Seminario 2
Almuerzo / Lunch
IMPACTO DE LOS PRINCIPALES CAMBIOS MEDIOAMBIENTALES SOBRE LA
MICROBIOSFERA / THE IMPACT OF MAJOR ENVIRONMENTAL CHANGES IN
THE MICROBIOSPHERE
Moderador / Chairperson: Ricardo Guerrero, Barcelona, Spain
Katia Koelle, Durham, USA
Impacto del cambio climático sobre la dinámica y evolución de las
enfermedades bacterianas / The impact of climate forcing on bacterial
disease dynamics and evolution
Many infectious diseases, both bacterial and viral, show within-year and betweenyear variability in the size of their outbreaks. Furthermore, many of these diseases
are caused not by a single pathogenic entity or strain, but by a collection of them
which we identify under one name. These strains change in frequency and
dominance over the years, such that the gene pool is continuously evolving. Here, I
will show how mathematical and statistical models can be used to understand some
of these dynamics and evolutionary patterns. Specifically, I will focus on the
bacterial pathogen cholera and how its patterns in Bangladesh can, in part, be
explained by climate variability. The patterns I will touch on include patterns of
biotype replacement caused by long-term changes in seasonal forcing and patterns
of interannual disease variability driven by rainfall, river discharge, and the El Niño
Southern Oscillation.
16:00
Juan-Luis Ramos, Granada, Spain
Impacto de la polución química sobre los microbios: bombas de eyección y
su papel en la supervivencia / Impact of chemical pollution on microbes:
Efflux pumps and their role in survival
To analyze bacterial responses to toxic chemicals we have carried out a series of
transcriptomic and proteomic analyses. Our results show that with toluene
transcription of the flagellar apparatus is inhibited and under those circumstances
bacteria use efflux pumps to expel the solvent and induce a specific catabolic
pathway to degrade the pollutant. Exposure to pollutants can lead to selective
resistance to a wide range of unrelated compounds such as antibiotics, dyes, etc.
16:30
Page Caufield, New York, USA
Trazabilidad de los patrones migratorios humanos a través de la flora
bacteriana oral / Tracking human migration patterns through oral bacterial
flora
Members of the human indigenous biota, specifically Streptococcus mutans,
colonizing the oral cavity, are transmitted vertically, mother to infant. Extending this
pattern on a larger scale has demonstrated clustering of clonal types within racial,
ethnic and geographic boundaries, suggesting coevolution has occurred between the
human host and it’s obligate bacterial parasite. Analysis of polymorphisms among
alleles of conserved genes in S. mutans reveal phylogenetic clustering of strains
that appear to parallel human racial/geographic cohorts. This approach supports the
notion of the “out of Africa” origin of modern humans.
17:00
Richard S. Ostfeld, New York, USA
Pérdidas en la biodiversidad e incremento de los microbios patógenos /
Biodiversity loss and the rise of pathogenic microbes
Many zoonotic, wildlife, and plant pathogens can infect several host species.
However, hosts differ strongly in their capacity to support population growth of the
pathogen. Some hosts act as reservoirs that amplify pathogens, whereas others act
as “dilution hosts” that can absorb but do not contribute pathogens. Reservoir
hosts tend to be abundant, widespread species that are resilient to human-caused
environmental degradation. In contrast, dilution hosts are often sensitive to
environmental degradation, disappearing when biodiversity is lost. This
presentation will describe case studies of diseases that are exacerbated when
human activities cause the loss of biodiversity.
17:30
Viernes / Friday 16th
SESIÓN 3/ SESSION 3
DIAGNÓSTICO DE LOS DAÑOS AMBIENTALES EN LOS SISTEMAS MICROBIANOS / DIAGNOSING
ENVIRONMENT-RELATED DAMAGES IN MICROBIAL SYSTEMS
Moderador / Chairperson: César Nombela, Madrid, Spain
08:30
Javier Arroyo, Madrid, Spain
Genómica y proteómica en la detección de daños en los sistemas microbianos /
Genomics and proteomics in the detection of damage in microbial systems
Yeasts are ubiquitous eukaryotic microorganisms exposed to highly variable
environment with respect to the presence of nutrients, temperature, pH, radiation,
oxygen and many other agents that could affect their viability. Yeast cells adapt
themselves to preserve cell integrity through transcriptional adaptation responses
that are mainly regulated by different MAPK signaling pathways. Genomics
approaches allowed us to characterize in more detail the mechanisms governed by
the cells to detect different stresses as well as the molecular mechanisms
regulating these adaptation responses.
09:00
Charles J. Dorman, Dublin, Ireland
Reguladores globales y adaptación ambiental en los patógenos Gram
negativos / Global regulators and environmental adaptation in Gramnegative pathogens
A powerful combination of single-gene studies and whole-genome approaches has
provided a wealth of information about the regulatory circuits used by bacteria to
adapt to the environmental changes that are encountered during infection. The
facultative intracellular pathogen Salmonella enterica will be used to illustrate how
global regulators such as the nucleoid-associated proteins Fis and H-NS collaborate
with fluctuations in the superhelicity of the DNA template to modify the gene
expression profile of the bacterial cell outside and inside the host.
87
09:30
Timothy G. Bromage, New York, USA
Complejidad del acoplamiento entre los sistemas micobianos y humano /
Complexity of coupled microbial and human systems
The biological flux of materials in the environment is a function of metabolism,
establishing for all organisms their fundamental life history strategies. A metabolic
theory of ecology observes this flux of materials along a continuum that connects
individual organisms to population and ecosystem levels or organization. As such,
the complexity of coupled microbial and human systems may link numerous pieces
of our world, such as gorilla conservation, environmental change, and exports of
manufactured goods into a global network.
10:00
10:30
CIENCIA PARA ACTUAR: VIGILANCIA Y BIO-REMEDIACIÓN DE LOS SISTEMAS MICROBIANOS
DAÑADOS / SCIENCE FOR INTERVENTION: SURVEILLANCE AND BIOREMEDIATION OF DAMAGED
MICROBIAL SYSTEMS
Moderador / Chairperson: Víctor de Lorenzo, Madrid, Spain
11:00
Frederick M. Cohan, Connecticut, USA
Cómo la sistemática bacteriana puede ayudar a evaluar las tendencias
ecológicas y evolutivas que imponen los cambios ambientales / How
bacterial systematics might help to evaluate ecological and evolutionary
trends imposed by environmental changes
To track evolutionary responses of bacterial to global change, microbiologists will
need a systematics aimed at discovering newly divergent populations with distinct
ecological traits (ecotypes). Traditional systematics is not up to this task, as the
species it recognizes are generally too broadly defined. Microbial systematists
generally cannot anticipate the ecological characteristics distinguishing young
ecotypes before the ecotypes are identified; so a universal molecular approach is
needed to identify them. What is needed are molecular markers that evolve rapidly
enough to distinguish very closely related populations, as well as an algorithm for
interpreting which clusters are most likely to correspond to ecotypes. “Ecotype
Simulation” analysis of DNA sequences of protein-coding genes in three bacterial
systems has demarcated dozens of putative ecotypes, many of which have been
confirmed as ecologically distinct; moreover, many such ecotypes are newly
divergent enough to be invisible to our current bacterial systematics. For example,
analysis of hot springs Synechococcus has identified extremely closely related
ecotypes that are subtly distinct in their temperature adaptations. While such a
sequence-based approach will not discover extremely young ecotypes, born during
the time of global warming, it should be able to track changes in abundance of
already existing ecotypes with different temperature and other adaptations. To
discover young ecotypes born during global warming, a more rapid molecular marker,
such as VNTR, will be required.
11:30
Alban Ramette, Bremen, Germany
Impacto del espacio, el tiempo y los ambientes complejos sobre las
comunidades microbianas / Impact of space, time and complex
environments on microbial communities
Microbial biogeographic analyses address how much historical vs. contemporary
factors can explain variation in the diversity patterns of microbial communities. In
this context, current work in soil and marine environments will be presented so as to
illustrate how microbial communities thriving in different habitats may be studied by
a combination of high throughput molecular techniques and powerful multivariate
analyses. The main amount of biological variation that can be explained by
environmental, temporal and spatial factors is thereby quantified and tested for
significance. This synthetic result thus serves as a precious indicator of our current
understanding and predictive abilities about changes in the microbial world.
12:00
Víctor de Lorenzo, Madrid, Spain
Organismos modificados genéticamente para la reparación medioambiental:
Qué se hizo mal y qué se puede hacer aun / GMOs for environmental
remediation: What went wrong and what can still be done
The expectations raised in the mid 1980s on the potential of genetic engineering for
in situ remediation of environmental pollution have not been entirely fulfilled. In the
environment, the new information born by the implanted genes and genetic circuits
must be stably inherited in the absence of any selective pressure, must not be
associated to antibiotics, and must not cause the loss of ecological fitness in the
carrier. The rise of Systems Biology and Synthetic Biology allows fresh approaches to
these thus far intractable problems.
12:30
13:00
Seminario 1
14:00
Seminario 2
Almuerzo / Lunch
MULTI-RESISTENCIA A FÁRMACOS EN TB, MALARIA Y VIH / MULTIDRUG RESISTANCE IN TB,
MALARIA AND HIV
Moderador / Chairperson: Gail Cassell, Indianapolis, USA
16:00
Gail Cassell, Indianapolis, USA
Multirresistencia a fármacos en tuberculosis, malaria, y VIH: Aspectos
comunes, magnitud del reto y consecuencias / Multidrug resistance in
tuberculosis, malaria, and HIV: Common themes, magnitude of the challenge,
and implication
Globally, tuberculosis is one of the leading causes of death due to an infectious
disease, second only to HIV/AIDS. A public health crisis is rapidly emerging due to
strains of Mycobacteria tuberculosis that are resistant to most, and in some cases all,
existing antibiotics. Genotyping of isolates indicates that in contrast to popular belief,
most of the cases are a result of ongoing transmission of drug resistant strains rather
than resistance being due to poor response to the initial treatment regimen or to an
inadequate regimen. These results have major public health policy implications.
Increasing resistance to anti-retroviral and anti-malaria drugs pose equal challenges.
Common themes and implications will be discussed.
16:30
Sebastien Gagneux, London, UK
El coste biológico de la resistencia a fármacos en Mycobacterium tuberculosis
/ Fitness cost of drug resistance in Mycobacterium tuberculosis
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR)
forms of Mycobacterium tuberculosis is threatening to make one of the most important
human infectious diseases untreatable. Using a combination of in vitro assays and
molecular epidemiological studies, we found that the competitive fitness and
transmissibility of M. tuberculosis varied as function of the specific drug resistanceconferring mutation and strain genetic background. Furthermore, our preliminary data
suggest that the fitness cost of drug resistance in M. tuberculosis can be mitigated by
compensatory evolution within a single patient. Our findings have implications for the
prediction the future of the MDR tuberculosis epidemic.
17:00
Dyann Wirth, Boston, USA
Diversidad genética del Plasmodium falciparum: Aproximación a la biología y
la resistencia del parásito a los fármacos / Plasmodium falciparum genetic
diversity: Insights into parasite biology and drug resistance
Dyann F. Wirth is Director of the Harvard Malaria Initiative, Chair of the Department of
Immunology and Infectious Diseases, and Richard Pearson Strong Professor of
Immunology and Infectious Diseases at the Harvard School of Public Health. She is an
expert in tropical disease and molecular microbiology, and has played a leadership role,
both in the research community and in the general public, in raising awareness of the
burgeoning problem of malaria and of malaria drug resistance. Malaria affects 200-300
million people worldwide, mostly children. A recipient of the Burroughs Wellcome
Award in Molecular Parasitology, she has also advised and consulted for organizations
such as the National Institutes of Health, the Institute of Medicine, and the World
Health Organization.
89
17:30
Michael Kozal, New Haven, CT, USA
Multirresistencia a fármacos en el VIH / Multidrug resistance in HIV
The development of antiretroviral therapy has led to a major reduction in mortality due
to HIV. However, HIV drug resistance has been shown to occur with all antiretroviral
agents. HIV drug resistance can affect the response to antiretroviral therapy and is
associated with increased mortality. The emergence of HIV drug resistance in persons
on therapy and the transmission of drug-resistant HIV strains to newly infected
persons are now major public health problems. HIV infection exists as a viral
quasispecies (a “swarm” of genetically diverse virus strains) in an infected person. All
the viral strains that make up the “swarm” in a person are not detected by the
standard resistance assays used in the clinic (current assays are typically restricted to
detecting resistant variants that make up >20% of the quasispecies). Recent data
suggests that resistant viral variants that make up as little as 1% of the viral
population in a HIV-infected person are clinically important as they can rapidly grow
under drug selection pressure and lead to therapy failure. This talk will address the
epidemiology and biologic mechanisms of HIV drug resistance and the new approaches
to detect and combat HIV drug resistance.
18:00
18:30
SEMINARIOS
Seminario 1
Ponente: Rafael Cantón, Madrid, Spain
Jueves 15, 12:30 h y Viernes 16, 13:00 h
Los genes de resistencia antibiótica en el medio ambiente / Antibiotic
resistance genes in the environment
Soil bacteria may contain antibiotic resistance genes responsible for different
mechanisms that permit to overcome the presence of natural antibiotics present in
the environment. This gene pool has been recently named resistome and its
components can be mobilized into the microbial community affecting humans.
Evidences of this transference have been suggested or demonstrated with newly
widespread genes in multidrug-resistance bacteria, such as certain extendedspectrum beta-lactamases genes (blaCTX-M), 16s RNA methylases (armA, rtmB) and
qnr genes.
Seminario 2
Ponente: Sara Soto, Barcelona, Spain
Migraciones y enfermedades infecciosas / Migrations and infectious diseases
Throughout history, the movement of people has played a critical role in the
transmission of infectious disease. Overall, migration of humans has been the
pathway for disseminating infectious diseases throughout recorded history and will
continue to shape the emergence, frequency, and spread of infections in geographic
areas and populations. However, globalisation can exacerbate the risk of spreading
infectious diseases. These effects are mediated not only through the movement of
people but also by the increased mobility of disease vectors, livestock and other
animals that may host zoonoses, as well as the greater propensity of food-borne
disease.


Conferencias: 30 minutos de conferencia y 30 minutos de discusión al finalizar cada sesión / 30-minute talk;
30-minute discussion after each session.
Seminarios: Duración, 1 hora: Exposición, 20 min; Coloquio con los asistentes, 40 min. Grupos reducidos
Fundación Lilly
Fernando Baquero, César Nombela, Gail Cassell,
José A. Gutiérrez-Fuentes
Información en: Tel: +34 91 781 50 70 – 71 www.fundacionlily.com ; [email protected]
ENGLISH <> SPANISH : TRADUCCIÓN SIMULTANEA <> SIMULTANEOUS TRANSLATION
PROVIDED
Julian Davies
Department of Microbiology and Immunology,
Life Sciences Institute, University of British
Columbia, Vancouver, BC, Canada.
[email protected]
Fernando Baquero
Servicio de Microbiología, Hospital Ramón y
Cajal, Madrid, Spain.
[email protected]
Andrés Moya Simarro
Instituto Cavanilles de Biodiversidad y Biología
Evolutiva, Universidad de Valencia, Valencia,
Spain.
[email protected]
José-Luis Martínez
Dpto. de Biotecnología Microbiana, Centro
Nacional de Biotecnología, CSIC, Cantoblanco,
Madrid, Spain.
[email protected]
César Nombela
Cátedra de Microbiología, Facultad de Farmacia,
Universidad Complutense de Madrid, Madrid,
Spain.
[email protected]
Ricardo Guerrero
Cátedra de Microbiología,
Universidad de Barcelona, Spain.
[email protected]
Katia Koelle
Department of Biology, Duke University,
Durham, USA.
[email protected]
Juan-Luis Ramos
Estación Experimental del Zaidín, Department of
Environmental Protection, CSIC, Granada, Spain.
[email protected]
Page W. Caufield
College of Dentistry, School of Medicine,
Department of Biology, New York University, NY,
USA
[email protected]
Richard S. Ostfeld
Institute of Ecosystem Studies, Sharon Turnpike,
Millbrook, NY, USA.
[email protected]
Javier Arroyo
Departamento de Microbiología II, Facultad de
Farmacia, Universidad Complutense de Madrid,
Madrid, Spain.
[email protected]
Charles James Dorman
Department of Microbiology, Trinity College Dublin, Dublin,
Ireland.
[email protected]
Timothy G. Bromage
Department of Biomaterials, New York University College of
Dentistry, NY, USA.
[email protected]
Victor de Lorenzo
Dpto. de Biotecnología Microbiana, Centro Nacional de
Biotecnología, CSIC, Cantoblanco, Madrid, Spain.
[email protected]
Frederick M. Cohan
Department of Biology, Wesleyan University, Middletown,
Connecticut, USA.
[email protected]
Alban Ramette
Max Planck Institute for Marine Microbiology, Bremen,
Germany.
[email protected]
Gail Cassell
Eli Lilly and Company, Lilly Corporate Center, Indianapolis,
IN, USA.
[email protected]
Sebastien Gagneux
Division of Mycobacterial Research
National Institute for Medical Research,
London, UK.
[email protected]
Dyann Wirth
Immunology and Infectious Diseases
Harvard School of Public Health, Boston, MA, USA.
[email protected]
Michael J. Kozal
Dept. Internal Medicine, Section of Infectious Diseases, Yale
University, New Haven, CT, USA
[email protected]
_________________________
Rafael Cantón
Servicio de Microbiología, Hospital Ramón y Cajal, Madrid,
Spain.
[email protected]
Sara Soto
Laboratorio de Microbiología, Hospital Clínico de Barcelona,
Barcelona, Spain.
[email protected]
91
A menudo se llama a la química la “ciencia central”, debido al papel que juega como conexión entre las ciencias "duras",
como la física, y las "blandas", como la biología o la medicina, facilitando los avances mas interesantes en la frontera
entre áreas científicas. La química facilita de esta manera contribuciones seminales a la biomedicina, contribuyendo a la
creación de nuevos fármacos.
La invención y desarrollo de un nuevo medicamento es un proceso largo, complejo, costoso y arriesgado que tiene pocos
ejemplos parangonables en el mundo industrial. Tanto históricamente, como en la actualidad, la creación de un nuevo
fármaco ha cabalgado sobre todo –aunque no únicamente- sobre la síntesis química. Así, los métodos de síntesis, a
través de los cuales los científicos pueden crear moléculas cada vez más complejas, se encuentran con frecuencia en la
base de los nuevos y cada vez más eficaces fármacos. De forma adicional, la actual miniaturización y automatización de
las técnicas de ensayo biológico están impulsando un avance paralelo en la mejora de la metodología de síntesis.
Este 13º Simposio Científico de la Fundación Lilly, “Química, Ciencia en la Frontera”, reúne a científicos con diferentes
visiones y culturas en su aproximación a la creación de nuevas moléculas. Desde el uso de técnicas fluorosas en paralelo
para obtener productos naturales hasta la química organometálica con todas sus posibilidades actuales que está
produciendo la rápida expansión de nuevos métodos sintéticos como nunca se había visto anteriormente. Desde la
catálisis en sus últimas aproximaciones hasta la síntesis enantioselectiva. Desde la química médica dirigida con precisión
a dianas escogidas hasta la biología química relacionada con la estructura del ADN. Desde los desarrollos de la química
supramolecular hasta la química de los catenanos, rotaxanos y máquinas moleculares. Los organizadores hemos
pretendido que a lo largo del programa haya siempre un equilibrio entre dos filosofías: una, que toma de la naturaleza
su fuente de inspiración, y otra, que hace uso de las nuevas herramientas que la ciencia pone en nuestras manos y en
nuestros laboratorios. Esperamos que esta combinación resulte en una oferta atractiva en relación con la química
moderna.
“QUÍMICA: CIENCIA EN LA FRONTERA”
 Presidido por Julio Álvarez-Builla, Jesús Ezquerra y Miguel Yus.
Durante el Simposio y a propuesta de la a propuesta de la Real Sociedad Española de Química, se hizo entrega
del Premio: Distinguished Career Award “Chemistry 2008”, al Profesor José Elguero Bertolini.
“Chemistry: science at the frontier". Monográfico del 13º Simposio Científico. Diciembre 2008.
-
los asistentes al Simposio. 3.500 ejemplares
-
93
-PROGRAMA-
Directores / Chairmen:
JULIO ÁLVAREZ-BUILLA, JESÚS EZQUERRA, MIGUEL YUS
Fecha / Date: April 17th & 18th, 2008
08:00
08:20
SESIÓN 1 / SESSION 1
08:40
Moderador / Chairperson: Ángeles Martínez-Grau and Jesús Ezquerra
Lilly Research Laboratories, Alcobendas, Madrid, Spain
Jean-Pierre Sauvage
Institut Le Bel, Strasbourg, France
Catenanos, Rotaxanos y Máquinas Moleculares / Catenanes, Rotaxanes
and Molecular Machines
(+ info)
09:30
Catenanes and rotaxanes are particularly attractive compounds, mostly in relation
to the novel properties that these molecules may exhibit. The use of Cu(I) as
template allows to entangle two organic fragments around the metal centre before
incorporating them in the desired catenane backbone. Based on this principle,
numerous multicomponent molecular assemblies have been made such as, in
particular, two-dimensional interlocking arrays. In relation to catenanes and
rotaxanes, a particularly promising area is that of synthetic molecular machines.
Various molecular machines have been elaborated and studied which contain
transition metals as key elements. The potential of such controlled dynamic
molecular systems will be discussed.
Dennis Curran
Department of Chemistry, University of Pittsburgh, Pittsburgh, Penn, USA
Síntesis de mezclas en fase fluorosa. Aproximación a la síntesis de
muestrotecas de estereoisómeros de productos naturales/Fluorous
Mixture Synthesis Approaches to Natural Product Stereoisomer Libraries
Because it separates primarily by fluorine content, fluorous reverse phase silica gel
can be used in a chromatographic mode to separate fluorous molecules from each
other. This separation forms the basis of new mixture synthesis techniques in
which members of a series of substrates are tagged with different fluorous tags,
mixed, carried through a series of reactions, and then separated based on the tag
prior to detagging. Recent fluorous mixture syntheses of stereoisomer libraries of
murisolins, passifloricins, and dictyostatins and other natural products will be
highlighted.
(+ info)
10:20
Coffee
95
10:50
(+ info)
11:40
(+ info)
Alois Fürstner
Max-Planck-Institut für Kohlenforschung, Mülheim/Ruhr, Germany
El impresionante poder de la metátesis / The Awesome Power of
Metathesis
The advent of well defined and highly tolerant catalysts for olefin metathesis,
introduced by the groups of Schrock and Grubbs in the early 1990’s, has
changed the way how organic chemistry is currently practiced. Our group has
helped to scrutinize this methodology for now more than a decade, inter alia by
the total synthesis of natural products of increasing complexity. This lecture will
summarize some of our recent projects in this field, which highlight the
awesome power of olefin metathesis and reveal some of the few remaining
limitations. In the second part of my seminar our work on alkyne metathesis will
be surveyed, which constitutes a complementary way to harness the inherent
advantages of metathetic transformations. The current status of this
methodology will again be illustrated by selected applications to natural product
chemistry.
Fernando Albericio
Institut de Recerca Biomèdica, IRB-PCB, Universidad de Barcelona, Spain
Nuevas aproximaciones a la síntesis de péptidos complejos / New
Approaches for the Synthesis of Complex Peptides
Recent years have witnessed a revival in the field of peptides. Success in the
field of peptide research is partly attributable to the fact that it is now possible
to synthesize almost any peptide on both small and large scales. In this
communication, several topics will be discussed. First of all, we will present a
short overview of the use of peptides in medicine. Next, the most used
synthetic strategies, which involve solid-phase, a combination of solid-phase
solution, and chemical ligation, will be discussed for the synthesis of complex
peptides from marine origin.
12:30
- Lilly Foundation Distinguished Career Award Ceremony
-
13:00
Lunch
Session 2
15:00
(+ info)
15:50
Chairperson: Rafael Suau
Dpto. Química Orgánica, Facultad de Ciencias de la Univ. de Málaga, Spain
Lutz F. Tietze
Institut für Organische und Biomolekulare Chemie, Universität Göttingen,
Germany
Reacciones dominó y múltiples catalizadas por Pd para la síntesis
eficiente de productos naturales y materiales / Domino and Multiple PdCatalyzed Reactions for the Efficient Synthesis of Natural Products and
Materials
Domino Reactions allow the synthesis of complex molecules in a highly efficient
way starting from simple substrates. They are of special interest for the
preparation of natural products and analogues which are important as lead
structures for the development of bioactive compounds. Moreover, they can also
be used for the synthesis of any type of material and in combinatorial
chemistry. The quality of a domino reaction can be correlated to the increase of
complexity in the process. In the lecture the synthesis of alkaloids, natural
chromans, steroids, tetracylines and molecular switches will be described.
Jacqueline K. Barton
California Institute of Technology, Chemistry, CA, USA
(+ info)
Transporte de carga a través de ADN, para dañar y reparar ADN / DNA
Charge Transport for DNA Damage and Repair
Many experiments have now shown that double helical DNA can serve as a
conduit for efficient charge transport reactions over long distances in vitro. This
chemistry is exquisitely sensitive to perturbations in the DNA base stack and
can be harnassed for sensitive diagnostics. Studies will be described to
characterize biological roles for DNA charge transport. This chemistry may be
used advantageously within the cell in long range signaling to DNA-bound
proteins, both to regulate transcription and to activate repair of base lesions
under conditions of oxidative stress. DNA charge transport chemistry provides
an opportunity to carry out redox chemistry at a distance.
16:40
Coffee
17:00
(+ info)
17:50
M. Christina White
Department of Chemistry, University of Illinois, IL, USA
Agilizando la síntesis a través de la oxidación C-H / Streamlining
Synthesis via C—H Oxidation
Although it has been well demonstrated that given ample time and resources,
highly complex molecules can be synthesized in the laboratory, too often
current methods do not allow chemists to match the efficiency achieved in
Nature. The discovery and development of highly selective C—H oxidation
methods, similar to those found in Nature, for the direct installation of oxygen
and nitrogen functionalities into allylic and aliphatic C—H bonds of complex
molecules and their intermediates will be presented. Unlike Nature which uses
elaborate enzyme active sites, we rely on the subtle electronic and steric
interactions between C—H bonds and small molecule transition metal complexes
to achieve high selectivities. Our current understanding of these interactions
gained through preliminary mechanistic studies will be discussed. Novel
strategies for streamlining the process of complex molecule synthesis enabled
by these methods will be presented.
Larry E. Overman
Department of Chemistry, University of California, Irvine, CA, USA
Estudios recientes en la síntesis total de alcaloides / Recent Studies in
Alkaloid Total Synthesis
The structural diversity of alkaloids is unparalleled among natural products. For
many years, unique alkaloid structures have stimulated the development in our
laboratories of new chemical transformations and new synthesis strategies. This
lecture will discuss our recent progress in developing concise synthesis
strategies for preparing several alkaloids having novel structures.
(+ info)
VIERNES/ Friday / 18th
Session 3
08:30
(+ info)
09:20
Chairperson: Miguel A. Yus
Dep. Química Orgánica, Facultad de Ciencias, Universidad de Alicante,
Alicante, Spain
Phil S. Baran
The Scripps Research Institute (TSRI), La Jolla, CA, USA
El ciclo catalítico de descubrimiento en la síntesis total / The
Catalytic Cycle of Discovery in Total Synthesis
Many would argue that the field of organic synthesis has made such
phenomenal advances over the past five decades that given unlimited
resources, the synthesis of almost any molecule is now possible. As such,
total synthesis is becoming increasingly focused on preparing natural
products in the most innovative and efficient manner possible. Selected
studies from our lab will be presented on the total synthesis of complex
natural products (see Figure below for selected targets)
Gregory C. Fu
Massachusetts Institute of Technology, Chemistry, MA, USA
Reacciones de acoplamiento catalizadas por Paladio y Níquel /
Palladium- and Nickel-Catalyzed Coupling Reactions
Despite the tremendous accomplishments that have been described in
the development of palladium- and nickel-catalyzed carbon–carbon bondforming processes, it is nevertheless true that many significant
opportunities remain. For example, to date the overwhelming majority of
studies have focused on couplings between two sp2-hybridized reaction
(+ info)
sites (e.g., an aryl metal with an aryl halide).
As of 2001, there were few examples of palladium- or nickel-catalyzed
coupling reactions of alkyl electrophiles. During the past several years,
we have pursued the discovery of palladium- and nickel-based catalysts
for coupling activated and unactivated primary and secondary alkyl
electrophiles that bear b hydrogens. Our recent efforts to develop
broadly applicable methods, including enantioselective processes, will be
discussed.
97
10:10
Jean-Pierre Genet
Ecole Nationale Supérieure de Chimie de Paris, Laboratoire de Synthèse
Sélective Organique et Produits Naturels, Paris, France
(+ info)
Nuevos desarrollos de catálisis organometálica en síntesis
orgánica / New Developments of Organometallic Catalysts in
Organic Synthesis
The lecture will focus on the progress that has been made in the following
areas:
(i) Design of of new chiral atropisomeric ligands: SYNPHOS® and
DIFLUORPHOS®.
(ii) Chemistry of new rhodium-catalyzed processes using the stable
organo trifluoro borates.
(iii)Developments of ruthenium-catalyzed asymmetric hydrogenation for
the synthesis of biologically active compounds.
11:00
Coffee
11:30
(+ info)
12:20
M. Carmen Carreño
Dpto. Química Orgánica (C-I). Universidad Autónoma de Madrid, Madrid,
Spain
Nuevas aplicaciones de quinonas y quinoles en síntesis asimétrica
/ New Applications of Quinones and Quinols in Asymmetric
Synthesis
The efficacy of sulfoxides in diastereoselective auxiliary-induced reactions
is nowadays well established. Their easy elimination and possible
transformation into other functions increase their synthetic usefulness.
This lecture will describe how we are using enantiopure sulfinyl quinone
and p-quinol derivatives to synthesize bioactive molecules and polycyclic
structures with helical chirality. Diels-Alder reactions and conjugate
additions are essential tools en route to our targets. Proper choice of the
partners allow domino reactions to occur, opening a rapid access to
structurally complex molecules in a highly stereocontrolled manner.
Steve G. Davies
Chemistry Research Laboratory, Department of Chemistry, Oxford
University, UK
Transformaciones estereoselectivas de Alilaminas /
Stereoselective Transformations of Allylamines
The amino diol motif is a recurring structural component in a diverse
range of biologically active natural products and synthesis molecules. The
asymmetric synthesis of a range of natural products and other highly
functionalized molecular architectures containing the amino diol unit,
including sphingosine, jaspine B, and polyhydroxylated pyrrolidines
utilizing a variety of synthetic methodology including asymmetric
conjugate addition of nitrogen nucleophiles, novel cyclisation strategies
and ammonium-directed dihydoxylation will be described.
(+ info)
13:15
Session 4
15:00
Lunch
Chairperson: Julio Álvarez Builla
Dpto. Química Orgánica, Facultad de Farmacia, UAH, Spain
Joe Shih
Lilly Research Laboratories, Eli Lilly, Indianapolis, USA
La evolución de la oncología en Lilly, desde el agente citotóxico
vectorizado (Alimta) a los inhibidores de kinasa/ The Evolution of
Lilly Oncology, from Targeted Cytotoxic Agent (Alimta) to Kinase
Inhibitors
This lecture will describe the evolution of the cancer drug discovery efforts
at Lilly Research Laboratories, Eli Lilly and Company, over the past forty
years. The oncology drug discovery endeavors at Lilly can be traced back to
the early 1970’s beginning from the isolation and discovery of Vinca
alkaloids (Vincristine and Vinblastine) from the Catharanthus roseus (L.) G..
This was then followed by the successful discovery and development of
novel anti-metabolites such as Gemcitabine (difluoro-nucleoside) and Alimta
(antifolate) in the 1980s and 1990s. The discovery history, mode of action
and some clinical development challenges of Alimta will be highlighted.
Finally, recent examples of kinase drug discovery and development efforts
(focus on PKC
 MAP
and p38
kinases) at Lilly will also be descr ibed.
Closure Conference
Jean-Marie Lehn
- Nobel Laureate in Chemistry 1987 Laboratoire de Chimie Supramoléculaire, Université Louis Pasteur,
Strasbourg, France
15:50
De la química supramolecular a la química constitucionalmente
dinámica / From Supramolecular Chemistry to Constitutional
Dynamic Chemistry Supramolecular chemistry is intrinsically a dynamic
chemistry in view of the lability of the interactions connecting the molecular
components of a supramolecular entity and the resulting ability of
supramolecular species to exchange their constituents. The same holds for
molecular chemistry when the molecular entity contains covalent bonds that
may form and break reversibility, so as to allow a continuous change in
constitution by reorganization and exchange of building blocks. These
features define a Constitutional Dynamic Chemistry on both the molecular
and supramolecular levels.
Applications of this approach in biological systems as well as in materials
science will be described.
(+ info)
Closure / Farewell
Julio Álvarez-Builla, Miguel Yus, Jesús Ezquerra, José A Gutiérrez-Fuentes
Conferencias: 40 minutos de conferencia y 10 minutos de discusión al finalizar cada conferencia /
40-minute talk; 10-minute discussion after each talk.
Julio Álvarez-Builla; Miguel Yus; Jesús Ezquerra;
José A Gutiérrez-Fuentes
Contacto Fundación Lilly:
María de Molina 3, 1º – 28006 Madrid – 91 781 50 70
Fax 91 781 50 79 – Email: [email protected] - www.fundacionlilly.com
Jesús Ezquerra
Lilly Research Laboratories
Alcobendas, Madrid, Spain
[email protected]
Jean-Pierre Sauvage
Institut Le Bel
Strasbourg Cedex, France
[email protected]
Dennis Curran
Department of Chemistry, Chevron
Science Center
Pittsburgh, USA
[email protected]
Alois Fürstner
Max-Planck-Institut für Kohlenforschung
Mülheim an der Ruhr, Germany
[email protected]
Fernando Albericio
IRB, Universidad de Barcelona
Barcelona, Spain
[email protected]
Rafael Suau
Dpto. Química Orgánica, Facultad de
Ciencias de la Universidad de Málaga
Málaga, Spain
[email protected]
Lutz F. Tietze
Institut für Organische und
Biomolekulare Chemie, Universität
Göttingen
Göttingen, Germany
[email protected]
Jacqueline K. Barton
Division of Chemistry and
Chemical Engineering
California Institute of
Technology
California, USA
[email protected]
M. Christina White
Department of Chemistry,
University of Illinois
Urbana, IL, USA
[email protected]
Larry E. Overman
University of California
California, USA
[email protected] /
[email protected]
Miguel A. Yus
Dep. Química Orgánica,
Facultad de Ciencias,
Universidad de Alicante
Alicante, Spain
[email protected]
Phil S. Baran
Department of Chemistry, The
Scripps Research Institute
La Jolla, California, USA
[email protected]
Gregory C. Fu
Massachusetts Institute of
Technology
Massachusetts, USA
[email protected]
Jean-Pierre Genet
Laboratoire de Synthèse Sélective Organique
et Produits Naturels, Ecole Nationale
Supérieure de Chimie de Paris
Paris Cedex, France
[email protected] / [email protected]
M. Carmen Carreño
Departamento de Química Orgánica,
Facultad de Ciencias, Universidad Autónoma
de Madrid, Spain
[email protected]
Steve G. Davies
Chemistry Research Laboratory, Department
of Chemistry, Oxford University
Oxford, UK
[email protected]
Julio Álvarez-Builla
Dep. Química Orgánica, Facultad de
Farmacia, Universidad de Alcalá de Henares
Madrid, Spain
[email protected]
Joe Shih
Lilly Research Laboratories, Eli Lilly
Indianapolis, USA
[email protected]
Jean-Marie P. Lehn -Nobel LaureateLaboratoire de Chimie Supramoléculaire,
Université Louis Pasteur
Paris, France
[email protected]
99
El objetivo principal del tratamiento de la diabetes es el control de los niveles de glucosa en sangre
sin caer en fenómenos de hipoglucemia. El tratamiento de la diabetes tipo 1 es con insulina, ejercicio y
dieta. En la diabetes tipo 2, el tratamiento procurará en primer lugar controlar el peso corporal, una dieta
diabética y el ejercicio físico. Cuando con estas recomendaciones no se consigan los objetivos terapéuticos
se utilizarán antidiabéticos orales, y solo cuando estos resulten insuficientes se considerará administrar
insulina.
El 14º Simposio Científico de la Fundación Lilly “DIABETES MELLITUS HOY”, incluye una mezcla de
científicos con diferentes culturas y puntos de vista en su aproximación a la investigación y la práctica
clínica de la diabetes mellitus. Es objetivo del Simposio acercar a los participantes una información de
novedosa y de primera mano sobre una enfermedad crucial como es la diabetes referida a su epidemiología
genética y molecular, su fisiopatología, los nuevos componentes como el óxido nítrico, las moléculas
inflamatorias, el estado protrombótico, la disfunción endotelial, o alteraciones relacionadas con las
dislipemias, la obesidad o la hipertensión.
Es propósito de la Fundación Lilly (www.fundacionlilly.com), en consonancia con sus objetivos
estatutarios, colaborar al mejor conocimiento de estos conceptos, y confiamos en lograrlo gracias al
notable plantel de personalidades que han aceptado nuestra invitación a compartir sus conocimientos e
ideas en cada una de las intervenciones programadas.
“DIABETES MELLITUS HOY”
 Presidido por Manuel Serrano Rios, Carlos Paya y José A. Gutiérrez Fuentes
Durante el Simposio y a propuesta de la a propuesta de la Sociedad Española de Diabetes, se hizo entrega del
Premio: Distinguished Career Award “Endocrinología y Nutrición. 2008”, al Profesor Manuel Serrano Ríos.
Monográfico del 14º Simposio Científico, editado como Suplemento de la Revista de
"Endocrinología y Nutrición”. Volumen 56, Monográfico 4, Noviembre 2009, (ISSN: 1575-0922)
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-
101
-PROGRAMA-
Directores / Chairmen:
MANUEL SERRANO RÍOS, CARLOS PAYA & JOSÉ A. GUTIÉRREZ FUENTES
Fecha / Date: November 13th & 14th, 2008
08:00
08:45
09:00
Conferencia Inaugural / Opening Lecture
Moderador / Chairperson: Carlos Paya
Edwin A M Gale. Bristol, UK
Tipos y clasificación de la Diabetes Mellitus. Visión crítica / Types and
Classification of Diabetes Mellitus. Critical overview
This presentation will consider the basis upon which we classify diabetes, and will ask
whether it is ‘fit for purpose’ in the light of current knowledge.
(+ info)
SESIÓN 1
09:40
Diabetes Mellitus Tipo 1 / Type 1 Diabetes Mellitus
Moderador / Chairperson: Manuel Serrano Rios
Gyula Soltész. Pecs, Hungary
Epidemiología global de la Diabetes Mellitus Tipo 1 en la infancia / Worldwide
childhood Type 1 Diabetes epidemiology
(+ info)
Type 1diabetes is the most common form of diabetes in childhood in most part of the
world. Wide variation exits between the incidence rates in different populations.
Typically, girls and boys are equally affected. In general, the incidence increases with
age, the incidence peak is in puberty. Prospective national and large international
registries (DIAMOND and EURODIAB) demonstrated an increasing trend in incidence in
most regions of the world over the last few decades and increases seem to be the
highest in the youngest age group. If current trends continue, a doubling of the new
cases in children under the age of five in Europe is anticipated.
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10:10
Massimo Trucco. Pittsburgh, Pa, USA
Interacción genes-medio ambiente en la Diabetes Mellitus Tipo 1 / Geneenvironment interaction in Type 1 Diabetes Mellitus
(+ info)
Type 1 diabetes is a multigenic, metabolic disorder, promoted by chronic autoimmune
destruction of the insulin-producing β cells in the pancreas. The cellular specificity
strongly implicates the fundamental role of β cell specific auto-antigens in the initiation
and progression of the disease. Immature hematopoietic cells are continuously
generated in the bone marrow and traveling in the blood eventually pass across the
thymus. Once in the thymus, they undergo positive and negative selections through
receptor interaction with fragments of proteins (peptides) constitutive of the tissues of
our bodies (“the self”), properly inserted in the peptide-binding grooves of the HLA
molecules. Indeed, the epithelial thymus is now known to express a wide array of selfantigens, including insulin. The molecular interactions that normally drive positive and
negative selection are altered by disease-associated HLA molecules so that self-reactive
T-cell clones are allowed to escape to the periphery, where start to kill the β cells,
eventually causing the onset of the disease.
10:40
11:00
Café / Coffee
Paolo Pozzilli. Rome, Italy
Historie natural e inmunopatogénesis de la Diabetes Mellitus Tipo 1 / Natural
history and immunopathogenesis of Type 1 Diabetes Mellitus
Type 1 Diabetes is an autoinmmune disease which results from an interaction between
genetic and environmental factors. The disease is highly heterogeneous, different
clinical types are detected suggesting different factors are involved in the
pathogenesis.
(+ info)
11:30
Philippe Froguel. Lille, France
Formas monogénicas de la Diabetes Mellitus. Actualización / Monogenic forms
of Diabetes Mellitus. An update
Most of what we know about the molecular mechanisms primary involved in beta-cells
defects in human T2D have been initially identified from the study of monogenic forms of
diabetes. Maturity Onset Diabetes of the young, Neonatal Diabetes and several
syndromes associated with diabetes both have a Mendelian origin and are transmitted
within families. The dissection of monogenic diabetes has brought breakthroughs about
beta-cell glucose sensing, the role of pancreatic transcription factors and of ions
channels in insulin secretion. It made possible a genetic diagnostic, and a new
pharmacologic approach of these forms of diabetes that led to more efficient targeted
treatments. Moreover, monogenic diabetes has contributed to understand better
common forms of T2D.
(+ info)
12:00
12:30
Discusión / Discussion General Topics 1
Seminario 1
13:30
SESIÓN 2
15:30
Seminario 2
Almuerzo / Lunch
Diabetes Mellitus Tipo 2 / Type 2 Diabetes Mellitus
Moderador / Chairperson: Ángel Sánchez Rodríguez
Nick Wareham. Cambridge, UK
Epidemiología de la Diabetes Mellitus Tipo 2 / Epidemiology of Type 2 Diabetes
Mellitus
This talk will include a summary of global evidence about the changing descriptive
epidemiology of type 2 diabetes and non-diabetic hyperglycaemia. Such a discussion is
fundamentally linked to questions about how we define disease. This issue is critical to
diabetes diagnosis and management since we have a gulf between definitions used and
applied in epidemiological and pathophysiological research, surveillance and clinical care.
Alternative future approaches including a possible alteration to how diabetes is defined
and how we might approach non-diabetic hyperglycaemia will be discussed.
(+ info)
16:00
Richard Bergman. Los Angeles, CA, USA
Resistencia insulínica y patofisiología de la Diabetes Mellitus Tipo 2 / Insulin
resistance and pathophysiology of Type 2 Diabetes Mellitus
(+ info)
16:30
Diabetes in increasing at an alarming rate in westernized countries, and this trend is
affecting countries in Asia and Africa as well. The increase is related to increased
adiposity, and it appears that adiposity is particularly detrimental to carbohydrate
homeostasis in certain populations, including in Japan, China, and India. To address this
trend it is important to understand the pathophysiological linkage between obesity,
insulin resistance and Type 2 diabetes mellitus. Visceral fat is particularly egregious; it
releases free fatty acids and other cytokines which cause steatosis and insulin resistance
of liver and muscle; it appears that much of the damage is done at night-time, and may
involve the sympathetic nervous system. Also critical is the failure of pancreatic betacells to respond adequately to insulin resistance, a failure which may have its origin in
genetic background. These interactions have been studied in animal models, and have
important implications in diabetes prevention and treatment.
Leif Groop. Malmö, Sweden
Bases genéticas de la Diabetes Tipo 2 / The genetic basis of Type 2 Diabetes
(+ info)
17:00
While the genetic causes of monogenic disorders have been successfully identified in the
past, the success in dissecting the genetics of complex polygenic diseases has until now
been limited. The picture has dramatically changed iduring the past two years and we
can now claim at least 20 genetic variants which are consistently associated with type 2
diabetes. For the first time we can with some confidence anticipate that the genetics of a
complex disease like type 2 diabetes really can be dissected.
Jose C Florez. Cambridge, MA, USA
Traslación clínica de los predictors genéticos de la Diabetes Mellitus Tipo 2 /
Clinical translation of genetic predictors for Type 2 Diabetes
(+ info)
17:30
The advent of genome-wide association scans (GWAS) has dramatically advanced our
ability to characterize the genetic architecture of type 2 diabetes. The development and
affordability of high-throughput genotyping platforms, the compilation of SNPs in public
databases, the assembly of large patient cohorts, the completion of the HapMap, the
generation of sophisticated analytical tools and the generous collaboratin among
diabetes genetics investigators have yielded a rich harvest of over a dozen previously
unsuspected type 2 diabetes genes. These genes, and those being discovered through
ongoing analytical integration of existing genome-wide datasets for type 2 diabetes and
related quantitative traits, highlight exciting new biology and open novel possibilities for
therapeutic intervention. Whether they will assume a beneficial role in disease prediction
above and beyond simple clinical risk factors remains an open question.
VIERNES/ Friday /14th
Seminario 1
08:30
SESIÓN 3
09:30
Ponente: Fernando Escobar-Jiménez
Guías clínicas en Diabetes Mellitus Tipo 1
/ Guidelines on Type 1 Diabetes Mellitus
Seminario 2
Ponente: José M Fernández-Real
Guías clínicas en Diabetes Mellitus Tipo 2 /
Guidelines on Type 2 Diabetes Mellitus
Enfermedades y complicaciones relacionadas con la Diabetes Mellitus /
Diabetes Mellitus related disorders and complications
Moderador / Chairperson: Rafael Carmena
Sudhesh Kumar. Coventry, UK
Obesidad y Diabetes Mellitus / Obesity and Diabetes Mellitus
(+ info)
Modern lifestyle with associated reduction in physical activity coupled with consumption
of energy dense food has resulted in an epidemic of obesity. Obesity is the strongest
acquired risk factor for diabetes and when combined with a family history of diabetes
dramatically increases the risk of diabetes when compared to individuals without these
risk factors. Deposition of fat in tissues like liver and muscle after exhausting all
available adipose tissue depots (largely a genetically determined trait) results in insulin
resistance and is an important mechanism for diabetes. Second, secreted proinflammatory factors from adipose tissue may cause diabetes. Changes in nutrient flux
from adipose tissue also contribute to obesity associated diabetes.
105
10:00
Marku Laakso. Kuopio, Finland
Alteraciones lipídicas y Diabetes Mellitus / Lipid disorders and Diabetes Mellitus
Lipid and lipoprotein levels are not abnormal in type 1 diabetes if glycaemic control is
adequate, and there are no signs of albuminuria or nephropathy. In contrast,
dyslipidaemia in type 2 diabetes is characterized by elevated levels of total and VLDL
triglycerides and low levels of HDL cholesterol. Dyslipidaemia is a strong risk factor for
cardiovascular disease in type 2 diabetes. Diabetic dyslipidaemia is treated with statins.
(+ info)
10:30
Paresh Dandona. New York, USA
Reactividad vascular en la Diabetes Tipo 2 / Vascular reactivity in Type 2
Diabetes
(+ info)
The inability of the circulation to respond to ischemic, anoxic, hypercapneic or thermal
stress with an increase in blood flow has now been established as a consistent defect in
patients with diabetes mellitus. This defect in vascular reactivity which impairs the ability
of diabetics to modulate blood flow according to stress related requirements adds to the
structural changes of atherosclerosis and microvascular disease known to be the
complications of diabetes. The absence of a compensatory increase in blood flow through
vasodilatory mechanisms would contribute to serious ischemic damage in critical
situations like acute coronary syndrome and transient ischemia of the brain. The known
defects of endothelial function including a reduction in NO and PGI2 generation and an
increase in TxA2 generation lead to a pro-constrictor state in diabetic blood vessels with
a relative loss of response to vasodilatory stimuli. The vasodilatory effect of insulin which
is dependent upon NO release from the endothelium is impaired in the insulin resistant
states of obesity and type 2 diabetes. In addition, there is an increase in the generation
of reactive oxygen species (ROS), oxidative stress and inflammation in both diabetes and
obesity. Oxidative stress reduces the bio-availability of NO since the superoxide radical
combines with NO to form peroxynitrate which does not have a vasodilatory effect and
instead has a cytotoxic effect. Inflammatory cytokines like TNFa reduce the expression
and activity of eNOS and thus the generation of NO. Thus, several mechanisms
contribute to the pathogenesis of the abnormal vascular reactivity observed in diabetes.
The reversal of this abnormality in the obese and type2 diabetics is important and this is
best achieved by thiazolidenediones which markedly reduce oxidative stress and
inflammation and restore the insulin sensitivity and endothelial function towards normal.
11:00
Café / Coffee
11:20
Paul K Whelton. Chicago, Ill, USA
Hipertensión en la Diabetes Mellitus / Hypertension in Diabetes Mellitus
(+ info)
In 2004, cardiovascular disease (CVD) resulted in 17.5 million deaths (7.6 due to CHD
and 5.7 million due to stroke). That number is projected to grow to 20 million by 2015
and 23.4 million by 2030. Hypertension and diabetes mellitus (DM) are two of the most
important major, modifiable risk factors for CVD and are commonly found in the same
patient; many times in combination with other elements of the metabolic syndrome.
Worldwide, the prevalence of hypertension is projected to increase from less than 1
billion to approximately 1.5 billion by 2025 and the prevalence of DM is expected to rise
from approximately 170 million to almost 400 million by 2030. Prevention and
treatment of hypertension and DM are essential elements of any meaningful initiative to
reduce the burden of CVD. Diuretics, alone or in combination with other
antihypertensive agents, are effective for treatment of uncomplicated hypertension in
persons with or without DM. ACEI and ARBs, alone or in combination with other agents,
are the preferred drugs for treatment of hypertension in persons with DM who have renal
damage. Overweight, obesity and physical inactivity are common causes of both
hypertension and DM. Lifestyle approaches aimed at weight loss and increased physical
activity are very effective in the prevention and treatment of both hypertension and DM.
Lifestyle change can be achieved through a combination of provider-patient interventions
and societal policies.
11:50
Paola Fioretto. Padova, Italy
El riñón en la Diabetes Mellitus / The kidney in Diabetes Mellitus
The clinical manifestations of diabetic nephropathy are similar in type 1 and type2
diabetes, while these renal lesions underlying the functional abnormalities may differ.
The kidney in diabetes is characterized by a constellation of lesions, comprising not only
the well known glomerular lesions, mesangial expansion and glomerular basement
membrane thickening, but also changes in the structure of podocytes, arterioles,
tubules, interstitium and in the glomerular-tubular junction. These topics will be
discussed, documenting the contribution of research kidney biopsy studies to the
understanding the natural history, pathogenesis and pathophysiology of diabetic
nephropathy.
(+ info)
12:20
12:40
- Lilly Foundation Distinguished Career Award Ceremony Conferencia Invitada / Invited Lecture
Moderador / Chairperson: José A Gutiérrez Fuentes
13:00
Salvador Moncada. London, UK
Óxido nítrico, mitocondria y bioenergía celular / Nitric Oxide, Mitochondria and
Cell Bioenergetics
Mitochondria generate energy in the form of ATP by oxidative phosphorylation. They also
play a role in apoptosis, and recent evidence indicates their involvement in cell
signalling. At physiological concentrations, the gaseous molecule nitric oxide (NO)
inhibits the mitochondrial enzyme cytochrome c oxidase (complex IV) in competition
with oxygen, and the interplay between the two gases may allow NO to act as a
physiological regulator of cell respiration. We are investigating the signalling and
bioenergetic consequences of this interaction in physiology and pathophysiology.
(+ info)
13:45
SESIÓN 4
15:30
Almuerzo / Lunch
Tratamiento de la Diabetes Mellitus / Diabetes Mellitus treatment
Moderador / Chairperson: Jose L Herrera-Pombo
Agustín Gómez de la Cámara. Madrid, Spain
Diabetes y factores de riesgo cardiovascular en España. El Estudio DRECE /
Diabetes and cardiovascular risk factors in Spain. The DRECE Study
(+ info)
16:00
The Diet and Cardiovascular Risk in Spain Study (DRECE) is an ongoing general
population based follow up cohort study started in 1991. The cohort is composed of
4783 individuals from 15 to 60 ages in the inception, and it is a representative sample of
the Spanish nationwide general population. Vital status and cause of death was provided
by the National Institute of Statistics. Mortality rates and risk factors were estimated by
Poisson and Cox regression, hazard ratio (HR), procedures respectively.
We found a mortality profile where cancer is the most frequent cause of death following
recent trends in western countries but we emphasize the role of Diabetes Mellitus and
Creatinine (probably as diabetes kidney damage surrogate variable) as early and strong
risk factors for cardiovascular mortality and therefore for all causes death. To the date,
no diet pattern or other cardiovascular risk factors appear associated. Diabetes emerges
as a prioritary target for action in Mediterranean countries.
Harold E Lebovitz. New York, USA
Recomendaciones actuales para el tratamiento de la Diabetes Tipo 2 / Present
recommendations in Type 2 Diabetes treatment
Considerations in the treatment of type 2 diabetes focus on treating the underlying
pathophysiologic defects. Combinations of agents should be used which reduce insulin
resistance while improving insulin secretion and restoring incretin actions. Recent
studies suggest that reducing weight should be a target as well as improving
cardiovascular risk factors. The use of all therapies must balance efficacy versus safety.
107
16:30
Antonio Ceriello. Coventry, Warwickshire, UK
Recomendaciones para el manejo de la glucemia postprandial /
Recommendations for postmeal blood glucose management
(+ info)
Prandial glucose regulation (PGR) is an emerging approach to treating type 2 diabetes
that emphasises the need for moderating the acute surges in plasma glucose levels that
follow meals. Mechanistic and epidemiological studies indicate that postprandial glucose
(PPG) contributes significantly to overall glycemic exposure and helps drive the
complications of diabetes. In particular, post prandial hyperglycemia is the most
important contributor to HbA1c, particularly when is lower than 7.5%. Therefore,
targeting postprandial hyperglycemia is mandatory for the achievement of HbA1c
targets. Numerous prandial therapeutics are now available, and an ever-growing
literature on their use shows that they are safe, effective, and convenient and that they
may offer distinct clinical benefits not found with treatments that target basal (fasting)
glycemia. IDF guidelines recognize the significance of PPG and the need to measure and
treat it. In these guidelines the cut-off for PPG is indicated in 7.8 mmol/ (140 mg/dl).
17:00
17:30
SEMINARIOS
Seminario 1
Ponente: Fernando Escobar-Jiménez, Granada, Spain
Guías clínicas en Diabetes Mellitus Tipo 1 / Guidelines on Type 1 Diabetes
Mellitus
(+ info)
Seminario 2
La Diabetes tipo 1 es una enfermedad que puede comenzar en los primeros periodos de
la vida. Además de Endocrinólogos y Pediatras, Ginecólogos e Internistas, son las
especialidades que se ocupan mas frecuentemente del los cuidados del paciente diabético
Estos cuidados deberemos adecuarlos al tipo de Diabetes, la actividad física, el trabajo, la
vida social y sus perspectivas de futuro. Sobre el tratamiento, las recomendaciones de
las Sociedades Científicas recogen una serie de posibilidades terapéuticas, que además
de la insulinoterapia, tienen en consideración otros aspectos como la existencia de
factores de riesgo asociados o la presencia de complicaciones micro-macrovasculares. La
Hb A1c < 7% debe ser un objetivo terapéutico.
Ponente: José M Fernández-Real, Gerona, Spain
Guías clínicas en Diabetes Mellitus Tipo 2 / Guidelines on Type 2 Diabetes
Mellitus
The Guidelines on Type 2 Diabetes Mellitus will be presented
(+ info)
•
Conferencias: 30-minute talks; 30-minute discussion after each session. English <> Spanish simultaneous
translation
•
Seminarios: Dirigidos a la discusión y orientación de aspectos prácticos relacionados con la prevención, el
diagnóstico y el tratamiento, en grupos reducidos. Sólo español / Only spanish
Manuel Serrano Ríos, Carlos Paya, José A Gutiérrez-Fuentes,
Jesús Reviriego.
Fundación Lilly: C/ María de Molina 3, 1º – 28006 Madrid – 91 781 50 70 - Fax 91 781 50 79 –
Email: [email protected] - www.fundacionlilly.com
Secretaría y apoyo logístico: Ana Isabel Moreno - Grupo 7 Viajes (c/ Medea 4, 3º A - 28037 Madrid)
Tel: 902 902 747 ext- 2 - Fax: 91 754 32 00 - [email protected]
We would like to welcome you to the 15th Lilly Foundation Simposium: “Molecular markers in cancer therapy: present
use and future perspectives”, a multidisciplinary meeting, organised by Lilly Foundation.
Cancer is a major health problem around the world. Cancer diagnoses around the world have been steadily increasing,
with 12 million new cases expected for 2009. World cancer deaths are expected to reach 7 million, according to the
World Health Organization, this reflecting the absence of effective therapies for the most common cancer types.
In this context, cancer therapy is slowly moving towards the design and application of targeted drugs, luckily some of
them already in use for routine clinical practice. Unfortunately, most of them are still at the bench or in the intricacies of
the pipeline that connects experimental laboratories, pharmaceutical companies and cancer clinical institutions.
The search for molecular markers identifying patients that may benefit from these targeted treatments is becoming an
exciting area of research. High-throughout molecular studies are offering also a rich source of information about
potential therapeutic targets and pharmacodynamic predictive markers.
Understanding of cancer and identification of therapeutic targets is being greatly facilitated by the International Cancer
Genome Project, and initiative that will be presented, together with some of the initial results, in this Meeting.
We are holding this 15th Lilly Symposium for bringing together leading scientists and clinicians with pharmaceutical
companies, to discuss candidate mechanisms and markers of drug resistance and therapeutic efficacy. We expect the
discussion to foster the efforts for integrating cancer research in the search of more efficient therapies.
Comité Científico Organizador, marzo de 2009
“MARCADORES MOLECULARES EN EL TRATAMIENTO DEL CÁNCER: UTILIDAD
ACTUAL Y PERSPECTIVAS”
 Presidido por los Profesores Miguel Ángel Piris y Manuel Morente.
 Celebrado en el EUROFORUM de San Lorenzo de El Escorial, Madrid.
 Fecha: 26 y 27 de marzo de 2009.
Durante el Simposio y a propuesta de la Asociación Española de Investigación contra el Cáncer, se hizo entrega
del Premio: Distinguished Career Award “CANCER 2009”, al Profesor Mariano Barbacid Montalbán.
Monográfico del 15º Simposio Científico, “Marcadores Moleculares en el tratamiento del
cáncer: utilidad actual y perspectivas”, Clinical & Translational Oncology -publicación oficial de
la Federación Española de Sociedades de Oncología (FESEO), Vol 11, Extraordinario 4,
Noviembre 2009, (ISSN: 1699-048X)
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Grabación del Simposio en www.fundacionlilly.com
109
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Chairmen / Directores: Miguel A Piris and Manuel Morente
Fecha / Date: March 26th & 27th, 2009
JUEVES/ Thursday, March / 26th
08:00
08:20
SESIÓN 1
08:40
Bienvenida y apertura / Welcome & Opening
CANCER GENOMICS I / GENÓMICA DEL CÁNCER I
Chairperson / Moderador: Mariano Barbacid, CNIO, Madrid, Spain
Tom Hudson, Ontario Institute for Cancer Research, Ontario, Canada
The International Cancer Genome Consortium / Consorcio Internacional del
Genoma del Cáncer
(+ info)
09:20
The International Cancer Genome Consortium (ICGC) was launched in April 2008 to
coordinate an international-scale research effort to understand the genomic,
transcriptomic and epigenetic changes involved in the major forms of cancer. The ICGC
will produce comprehensive catalogues of the full range of genetic mutations involved
in the world’s major types of cancer, with key factors being the ability to detect all
mutated cancer genes, data at the level of individual DNA bases, application of
common standards for pathology and technology and comparison data from matched,
non-tumor tissue. This information will lead to better ways of diagnosing, treating and
preventing cancer.
Victor E Velculescu, Johns Hopkins, Baltimore, MD, USA
The genomic landscapes of human cancer / Panorámicas genómicas del
cáncer humano
(+ info)
10:10
It is generally accepted that cancer is a disease caused by accumulation of mutations
in specific genes. These tumor-specific mutations provide clues to the cellular
processes underlying tumorigenesis and have proven useful for diagnostic and
therapeutic purposes. To date, however, only a small fraction of the genes has been
analyzed and the number and type of alterations responsible for the development of
common tumor types are unknown. We have recently begun a systematic study of the
cancer genome through analysis of the majority of protein coding genes in breast,
colorectal, pancreatic and brain cancers. These analyses have identified a wealth of
new genes and pathways that had not been previously linked to human cancer. Our
studies define the genetic landscape of human cancers, provide new targets for
personalized intervention, and open fertile avenues for basic research in tumor biology.
Rene Bernards, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Finding biomarkers of drug resistance using functional genetic approaches /
Identificación de biomarcadores de resistencia farmacológica mediante
genómica funcional
Targeted cancer therapies, like conventional cancer therapies, also suffer from the
development of resistance. In my laboratory, we use large-scale loss of function
genetic screens to find genes whose suppression causes resistance to targeted cancer
drugs. Such genes are of interest because they are modulators of the pathway that is
targeted by the drug, but also because these genes are potential biomarkers to predict
responses to these drugs in the clinic.
(+ info)
10:40
Café / Coffee
111
SESIÓN 2
11:10
CANCER GENOMICS II / GENÓMICA DEL CÁNCER II
Chairperson / Moderador: Miguel A Piris, CNIO, Madrid, Spain
Miguel A Piris, CNIO, Madrid, Spain
Targets in B-cell lymphoma / Dianas en los linfomas de células B
Lymphoid neoplasms are a heterogeneous group of lymphoproliferative malignancies
with differing patterns of behaviour and responses to treatment. Standard
treatments (cytotoxic therapy and immunotherapy) fail to cure roughly half of the
patients, leading also to side effects with significant morbidity. Data generated by
high-throughput and functional studies are showing that B-cell receptor (BCR)
provides the neoplastic B-cells with essential survival signalling. Our effort is
currently aimed to target signalling pathways and genes coupled to BCR.
(+ info)
11:50
Todd R Golub, Harvard Medical School, Boston, MA, USA
Genomic signatures of cancer / Patrones genómicos del cáncer
Comprehensive views of the cancer genome are now becoming feasible and have
potential for significant impact on the development of cancer therapeutics. Data will be
presented that illustrate the ability to generate genome-wide data at the level of DNA,
mRNA (including profiling of routinely-collected formalin-fixed paraffin-embedded
tissues), and the phosphoproteome. Use of such data for the development of
diagnostic and prognostic biomarkers will be presented, as will the use of these
genomic signatures as a read-out for small molecule screens.
(+ info)
12:30
Matthew Meyerson, Harvard Medical School, Boston, MA, USA
Genomic alterations in human cancer / Alteraciones genómicas en el cáncer
humano
(+ info)
13:10
Cancer is a disease of the genome. High-throughput genome analysis tools now enable the
detection of somatic alterations in cancer cells including point mutations, copy number alterations,
translocations, and infections. To find copy number alterations, we have now analyzed over 2,600
cancer samples with arrays representing 250,000 mapped single nucleotide polymorphisms (SNPs),
or most recently, over 1.8 million mapped probe sets. Major discoveries include the identification of
lineage-specific amplification of the NKX2-1 gene in human lung adenocarcinoma (Weir et al.,
2007) Most recently, we have identified a counterpart amplified gene in squamous cell carcinomas.
To find mutations, we are performing systematic sequencing of selected gene families. Here, major
discoveries include activation mutations of the epidermal growth factor receptor tyrosine kinase
gene, EGFR, in human lung adenocarcinomas (Paez et al., 2004) and glioblastomas, the fibroblast
growth factor receptor 2 gene, FGFR2, in endometrial carcinomas (Dutt et al., 2008), and the
anaplastic lymphoma kinase, ALK, in neuroblastomas (George et al., 2008). EGFR, FGFR, and ALK
inhibitors respectively kill cells bearing these mutations. Furthermore, we have identified a total of
26 genes that are recurrently mutated in lung adenocarcinoma (Ding et al., 2008). To further
systematic genome discovery in well-annotated cancers, the National Institutes of Health have
established “The Cancer Genome Atlas” project. This consortium has now completed preliminary
analyses of 206 glioblastoma tumor DNA and RNA specimens and identified significant genomic
alterations including mutation of the PI3 kinase regulatory subunit gene, PIK3R1 (TCGA Network,
2008).
- Lilly Foundation Distinguished Career Award Ceremony POSTERS SESSION
13:40
SESIÓN 3
15:20
Almuerzo / Lunch
CANCER BIOMARKERS / BIOMARCADORES DE CÁNCER
Chairperson / Moderador: Ramón Colomer Bosch, M.D. Anderson, Madrid, Spain
Manuel Morente, CNIO, Madrid, Spain
Quality in tumor samples. A limiting step in cancer research / Calidad de las
muestras biológicas. Un factor limitante en investigación oncológica
(+ info)
Translational cancer research is highly dependent of series of cases including high quality
samples and their associated data. An easier access to these samples for the scientific
community is considered as the main bottleneck for research for health, and biobanks are
the most adequate site to try to resolve this issue. However, biobanks should not be
considered a static activity. On the contrary, biobanking is a young discipline which need
continuously evolve according to the permanent development of new techniques and new
scientific goals.
To accomplish current requirements of the scientific community biobanks need to face some
essential challenges including an appropriate design including networking, harmonized and
more suitable procedures, and sustainability, all of them in the framework of their ethic,
legal and social dimensions.
16:00
Rafael Rosell, Germans Trias i Pujol Hospital, Barcelona, Spain
Therapy response predictors in lung cancer / Predictores de respuesta terapéutica en
cáncer de pulmón
(+ info)
16:40
17:00
Aberrant signaling generated by the activation of multiple pathways occurs in cancers and
contributes to their growth, invasion and survival. Lung cancer-specific EGFR mutations
represent a new paradigm of genotyping. In 217 patients with multiple metastases, daily
erlotinib attained a 70% response rate, a 14-month time to progression, and a 27-month
median survival. Central to DNA damage response is the breast cancer gene 1 (BRCA1). The
predictive value of the BRCA1-RAP80-Abraxas complex was examined in metastatic lung
cancer patients. A sub-group of patients attained an unprecedented time to progression of 14
months and median survival not reached. Genotyping for appropriate targeted therapy and
customized chemotherapy can improve outcomes in several tumors.
Café / Coffee
Jose Costa, Yale University School of Medicine, New Haven, CT, USA
Tumor biomarkers in the century of Systems Biology / Biomarcadores tumorales en
el siglo de la Biología de Sistemas
Novel technologies and computational biology make it possible to begin to deconvolute the
complexity of cancer. The promise and challenges of systems biology for the field of
biomarkers will be discussed with an emphasis on new multiparametric tests and their use in
the cancer clinic.
(+ info)
17:40
Dan Theodorescu, University of Virginia Health Sciences Center, Charlottesville, VA, USA
COXEN-A way forward in personalized cancer therapy and drug discovery /
COXEN-A en terapia oncológica personalizada y descubrimiento de nuevas drogas
We demonstrate a novel, facile yet powerful approach to biomarker derivation that identifies
patients most likely to benefit from selected multi-agent therapy. Use of such tools, provides a
robust and generalizable approach to personalized cancer therapy with far reaching
applications in drug discovery, drug salvage and forecasting of novel single and combination
drug effectiveness in cancer patients.
(+ info)
VIERNES/ Friday, March /27th
SESIÓN 4
08:20
MOLECULAR TARGETS / DIANAS MOLECULARES
Chairperson / Moderador: Juan A Velasco, Lilly Research Labs, Madrid, Spain
Mariano Barbacid, CNIO, Madrid, Spain
Mouse tumor models and target validation / Modelos tumorales en ratones y
validación de dianas
(+ info)
To date, more than 500 genes have been found mutated in human cancer, thus providing a
wealth of therapeutic targets. Unfortunately, only a handful of these mutated genes encode
druggable products. Moreover, even in those the cases in which the mutated protein can be
pharmacologically inhibited (protein kinases, growth factors, receptors, etc.), the degree of
therapeutic efficacy observed has been rather modest, with the exception of Gleevec and
possibly Herceptin. A plausible explanation for these observations has been recently provided
by sequencing cancer genomes. Advanced tumors carry mutations in multiple pathways, thus
suggesting that successfully cancer therapies will require combinations of drugs capable of
blocking two or possibly more distinct pathways. In order to devise better strategies to block
oncogenic signaling, we have developed mouse tumor models that faithfully resemble those
observed in human patients. These mice can be endowed with conditional mutations whose
activation specifically ablates putative therapeutic targets. I will present our most recent
results following these basic strategies to evaluate the therapeutic effect of ablating the Raf,
Mek and Erk kinases as well as the cell cycle Cdks (Cdk2, Cdk4 and Cdk6) in K-Ras induced
NSCLCs.
113
09:00
Robert Kerbel, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
Some mechanisms and consequences of antiangiogenic targeting of the VEGF
pathway in cancer / Algunos mecanismos y consecuencias de la actuación a través
de VEGF como diana de inhibición de angiogénesis en cáncer
Bedside to bench translational studies will be summarized with respect to a number of
important questions which have emerged from the clinical use and benefits of approved
antiangiogenic drugs. The research summarized is devoted to addressing some of the reasons
for the thus far transitory and modest benefits of antiangiogenic therapies for the treatment of
advanced metastatic disease. Some strategies for improving antiangiogenic therapies will be
outlined such as combination with other treatments, e.g. metronomic low-dose chemotherapy.
(+ info)
09:40
Kari Alitalo, Biomedicum Helsinki and the Haartman Institute, University of Helsinki, Finland
Targeting VEGF receptor pathways for inhibition of angiogenesis, lymphangiogenesis
and metastasis / El receptor de VEGF como diana de inhibición de angiogénesis,
linfangiogénesis y metástasis
(+ info)
Angiogenesis and permeability of blood vessels are regulated by vascular endothelial growth
factor (VEGF) via its two receptors VEGFR-1 and VEGFR-2. VEGFR-3 does not bind VEGF and
its expression becomes restricted mainly to lymphatic endothelia during development. We have
purified and cloned the VEGFR-3 ligand, VEGF-C. VEGF-C overexpression induces
lymphangiogenesis and growth of the draining lymphatic vessels, intralymphatic tumor growth
and lymph node metastasis in several tumor models. Furthermore, VEGFR-3 inhibitors bloc
lymphatic metastasis. These results together with recent clinical cancer studies indicate that
paracrine signal transduction between tumor cells and the lymphatic endothelium is involved in
lymphatic metastasis of human cancers. We have also recently found a role for VEGFR-3
signaling in settings of physiological and pathological angiogenesis in mice.
Café / Coffee
10:20
10:40
Francisco Real, CNIO, Madrid, Spain
Targeting the PI3K pathway in bladder cancer: different targets for different tumors?
/ La vía de PI3K en cáncer vesical: ¿dianas diferentes para tumores diferentes?
The PI3K pathway is involved in a wide variety of human cancers. In the bladder, there is
evidence for PI3K/mTOR activation in a large fraction of both non-muscle invasive and muscleinvasive tumors. PIK3CA mutations are very common in the former but they are rare in
muscle-invasive tumors. By contrast, PIK3CA gains and PTEN losses are rare in low grade,
non-muscle invasive, tumors and common in muscle-invasive cancers. It is crucial to
determine whether different genetic alterations have a differential effect on sensitivity to drugs
targeting PI3K/mTOR for rational clinical trial design.
(+ info)
11:20
Jonathan Yingling, Lilly Research Labs, Eli Lilly & Co. Corporate, Indianapolis, USA
Translating innovation: PK/PD driven drug discovery and patient tailoring in
oncology / Aplicando la innovación: descubrimiento de drogas en oncología a través
de PK/PD y adaptación al paciente individual
The pharmaceutical industry finds itself at a crossroads that requires transformational
approaches to meet the ever-increasing needs of patients, providers and payors. The
emergence of genomic technology has fundamentally changed oncology drug discovery and
provided unprecedented opportunities for new target discovery and validation as well as
“tailoring” to optimize patient outcomes. I will highlight the Lilly oncology strategy for
capitalizing on these breakthroughs and present 2 specific examples of portfolio assets that
have moved forward into the Lilly development pipeline and have the potential to significantly
improve the treatment of cancer.
SESIÓN 5
12:00
MicroRNAs AND EPIGENETICS / MicroRNAs Y EPIGENÉTICA
Chairperson / Moderador: Hernán Cortés Funes, Hospital 12 de Octubre, Madrid, Spain
Manel Esteller, Instituto de Investigaciones Biomédicas de Bellvitge (IDIBELL), Barcelona,
Spain
Cancer Epigenetics: from the bench to the bedside / Epigenética del cáncer: del
laboratorio a la cabecera del paciente
Cancer is an epigenetic disease characterized by the breakdown of the DNA methylation and
histone modification patterns. The stability of our genome and correct gene expression are
maintained in large measure thanks to a perfectly pre-established pattern of DNA methylation
and histone modifications. Both of them control the activity of a third component of the
epigenetic landscape, non-coding RNAs, particularly microRNAs that are also disrupted in
human cancer.
(+ info)
12:40
Jean-Pierre Issa, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
Epigenetic therapy: from promise to reality / Terapia epigenética: desde la promesa a
la realidad
Over the past decade, epigenetic changes such as alterations in DNA methylation and histone
modifications have been well described in cancer and are now recognized as targets of therapy
(epigenetic therapy). The aim of epigenetic therapy is to reverse epigenetic changes and
reactivate important genes thereby modifying the malignant phenotype and inducing clearance
of the malignant clone by various mechanisms. DNA methylation inhibitors and histone
deacetylase inhibitors have already shown impressive activity in subsets of patients with
leukemia. The field is moving forward into solid tumors, and in parallel, other epigenetic targets
are being identified and targeted with drugs.
(+ info)
13:20
Reuven Agami, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Cancerous microRNAs and regulatory RNA binding proteins / MicroRNAs en cáncer y
proteínas reguladoras de RNA-binding
(+ info)
MicroRNAs (miRNAs) are potent post-transcriptional regulators of protein coding genes.
Patterns of mis-expression of miRNAs in cancer suggest key functions of miRNAs in
tumorigenesis. In the past we set up experiments to identify miRNAs and identified miR-372,
miR-221 and miR-135 families as promoting tumor growth and metastasis. These miRNAs are
oncogenes as they are deregulated in various types of cancers, target tumor suppressors and
their inhibition reverts cancerous phenotypes. Interestingly, little is known about the
mechanisms controlling the expression and activity of miRNAs. This regulation is of outmost
importance due to the role miRNAs have during normal development and tumor progression.
Close inspection of miRNA-target sites on mRNAs revealed to us that occasionally sequences in
their vicinity are highly conserved throughout evolution. We therefore hypothesized that
conserved regions in mRNAs may serve as docking platforms for modulators of miRNA activity.
This led us to hypothesize that RNA-binding proteins could influence miRNA function. Modes of
this regulation will be discussed in this meeting.
POSTERS SESSION
14:00
SESIÓN 6
15:30
Almuerzo / Lunch
TARGETED THERAPY, EXAMPLES / TERAPIA DIRIGIDA A DIANAS, EJEMPLOS
Chairperson / Moderador: Eduardo Díaz Rubio, Hospital Clínico San Carlos, Madrid, Spain
Pierre Laurent-Puig, INSERM U775, Université Paris-Descartes, Paris, France
Prognostic factor in patients with advanced colorectal cancer treated with cetuximab
/ Factor pronóstico en pacientes con carcinoma colorrectal avanzado tratado con
cetuximab
We recently enlightened the role of the KRAS oncogene mutation as a marker of the resistance
to EGFR antibodies. The presence of KRAS mutations was significantly associated with an
absence of response to anti-EGFR monoclonal-antibody-based treatments. They are now
restricted to patients with a tumor with a non-mutant KRAS gene. However, only 50% of the
patients in this latter group give an objective response and other markers bring new
informations.
(+ info)
115
16:10
Josep Baselga, Vall d’Hebrón Hospital, Barcelona, Spain
Targeting HER2 in Breast Cancer. Novel therapies and mechanisms of resistance /
Apuntando a HER2 en cáncer de mama. Nuevos tratamientos y mecanismos de
resistencia
Aberrant receptor expression and/or functioning of the human epidermal growth factor receptor
(HER) family plays a critical role in the development and evolution of cancer. Inhibiting the
signalling activity of individual receptors in this family has advanced the treatment of a variety
of human cancers. In my presentation I will re-evaluate the role of two critical family
members, HER2 and HER3, and explore the mechanisms of action and preclinical/clinical data
for new therapies targeting signalling through these pivotal receptors. These new therapies
include tyrosine kinase inhibitors, antibody–chemotherapy conjugates, heat shock protein
inhibitors and antibodies that interfere with HER2:HER3 dimers.
(+ info)
16:50
Maria S. Soengas, CNIO, Madrid, Spain
Therapeutic windows for melanoma treatment / Ventanas terapéuticas para el
tratamiento del melanoma
(+ info)
17:30
Melanoma progression is invariably associated with multiple defects in apoptotic pathways. This
knowledge provides the platform for rational drug design. However, genetically targeted
therapies have not yet been proven effective in vivo. Therefore, melanomas may possess yet
unidentified mechanisms of cells survival. We have recently identified new roles of autophagy
(self cannibalism) underlying melanoma chemoresistance. Here we will report the
characterization of compounds able to rewire autophagy programs in melanoma cells to inhibit
tumor progression selectively (i.e. without affecting the viability of normal cell compartments).
We will present cellular and animal models that support selective autophagy induction as a
therapeutic window for intervention in melanoma.
Manuel Hidalgo, Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors / Inhibidores de
la tirosina-kinasa del receptor del factor de crecimiento epitelial (EGFR)
1 Review Current Status of EGFR Biology
2 Review State of the International Clinical Applications
3 Summarize New Agents and Therapeutic Strategies
(+ info)
18:10
− Conferencias: 30-minute talks; 10-minute discussion after each talk. English <> Spanish simultaneous translation.
− Posters: Permanent exhibition, attended by the authors at least on designed time periods / Exhibición permanente,
atendidos por los autores al menos durante las horas señaladas.
Miguel A Piris, Manuel Morente y José A Gutiérrez-Fuentes
EUROFORUM INFANTES
SAN LORENZO DE EL ESCORIAL, MADRID
Fundación Lilly: C/ María de Molina 3, 1º – 28006 Madrid – 91 781 50 70 - Fax 91 781 50 79 –
Secretaría y apoyo logístico: Ana Isabel Moreno - Grupo 7 Viajes (c/ Medea 4, 3º A - 28037 Madrid)
Tel: 902 902 747 ext. 2 / Fax: 91 754 32 00 / [email protected]
La enfermedad coronaria es una de las principales causas de muerte y de consumo de recursos sanitarios en los
países desarrollados. En España, aunque su incidencia sea inferior a la de otros países europeos, también
representa un importante problema sanitario, ya que, siguiendo la tendencia occidental, también es la primera
causa de muerte en hombres, y en algunas comunidades incluso en mujeres.
El estudio DRECE ha puesto de manifiesto, que el perfil lipídico español no es significativamente distinto al de
otras comunidades occidentales, a excepción de una concentración de colesterol de HDL (cHDL) algo más elevada,
lo que no representa en sí mismo un hecho diferencial con otras poblaciones como la inglesa, en que la morbimortalidad coronaria es considerablemente superior a la española. No obstante, las diferencias en el impacto de
la enfermedad coronaria en España siguen sin tener una explicación clara. Algunos asumen la existencia de un
efecto protector (genes, hábitos de vida, dieta española, ...), otros, consideran que simplemente estamos ante una
fase de latencia relacionada con nuestra historia reciente, y otros, por fin, dudan incluso de que esta diferencia
sea real.
A la luz de los más recientes avances, este 16º Simposio pretende aportar a la audiencia los últimos conocimientos
sobre la importancia de la alimentación en estos procesos y como ésta puede condicionar el desarrollo de la
aterosclerosis y otras enfermedades.
Particular atención se prestará al papel que en la formación de los ateromas juega el endotelio, las señales
moleculares, las lipoproteínas, el estrés oxidativo, o la coincidencia de diferentes patologías en el llamado
Síndrome Metabólico. Sólo a través de su conocimiento y comprensión podremos plantearnos un diagnóstico
adecuado y un tratamiento consecuente y eficaz para la enfermedad.
“ALIMENTACIÓN LÍPIDOS Y ATEROSCLEROSIS”
 Presidido por Carlos Macaya, Jesús Millán y José A. Gutiérrez-Fuentes.
 Celebrado en el EUROFORUM de San Lorenzo de El Escorial, Madrid.
Durante el Simposio y a propuesta de la Sociedad Española de Aterosclerosis y de la Sociedad Española de
Cardiología, se hizo entrega del Premio: Distinguished Career Award “Cardiovascular Diseases 2009” al Profesor
Alfonso Castro Beiras
"Alimentación, Lípidos y Aterosclerosis". Monográfico del 16º Simposio Científico, publicado
como Suplemento de la revista “Clínica e Investigación en Arteriosclerosis”. Volumen 22,
Extraordinario 2, Diciembre 2010, (ISSN: 0214-9168)
-
-
117
-PROGRAMA-
Directores / Chairmen: Carlos Macaya, Jesús Millán, José A. Gutiérrez-Fuentes
Lugar / Place: San Lorenzo de El Escorial, Madrid
Fecha / Date: November 5 & 6th, 2009
JUEVES/ Thursday, November / 5th
08:15
08:30
Session 1
08:45
NUTRICIÓN, LÍPIDOS Y ATEROSCLEROSIS / NUTRITION, LIPIDS AND
ATHEROSCLEROSIS I
Moderador / Chairperson: José A. Gutiérrez-Fuentes. Fundación Lilly, Madrid, Spain
Elaine Holmes
Department of Biomolecular Medicine, Imperial College London, London, UK
Evolución del microbioma humano, salud y predisposición a enfermedades / Human
microbiome evolution, health and predispositions to diseases
(+ info)
09:15
The complex interplay between human metabolism, nutrition and disease is influenced by the
gut microbiota, which have co-evolved with their host. Metabolic profiling studies can be used
to disentangle the various gene-environmental interactions and to explore the role of the
microbiome in relation to nutrition, obesity and cardiovascular disease. Here an introduction to
the basic analytical technology is provided followed by specific illustrations of application drawn
from a mixture of animal models, targeted clinical studies and epidemiological cohorts.
Particular focus will be placed on integration of metabolomic and metagenomic data.
G. Harvey Anderson
Department of Nutritional Sciences, University of Toronto, Toronto ON, Canada
Patrones dietéticos, funcionalidad de los alimentos y enfermedad crónica / Dietary
patterns, food functionality and chronic disease
(+ info)
09:45
Global dietary guidance suggests the Western Dietary pattern is a major cause of chronic
disease. Many of its traditional foods have been identified by epidemiology as risk factors. Yet
international cardiovascular disease statistics provide an obvious challenge to these
assumptions. For example, Canadians have a Western Dietary pattern but die from
cardiovascular disease (CVD) at a rate 60% less than Americans, with a similar dietary pattern.
Canadians have CVD death rates similar to Japan, France, and Spain, countries with very
different dietary patterns and eating behaviors. Thus it is clear that a greater emphasis needs
to be placed on understanding the role of physiological functionality of food, food components
and food behavior as health determinants.
J. Alfredo Martínez
Dept. of Physiology and Nutrition, University of Navarra, Pamplona, Spain
Respuesta genotipo-dependiente a la dieta: Hacia una nutrición personalizada en el
obeso / Genotype-dependent response to diets: Towards personalized nutrition in the
obese
(+ info)
10:15
Obesity as a complex syndrome with a multifactorial origin may be explained in some circumstances by
monogenic mutations, but in most cases appears as a polygenic condition, which is additionally affected by a
myriad of environmental influences (dietary and physical activity patterns). Identification of candidate genes
may allow providing individual specific recommendations (dietary advice and/or drug therapy) to achieve
effective weight loss and successful long-term maintenance of weight loss, on the basis of an identified
genetic susceptibility. However, at this moment it is premature to offer targeted obesity therapy based on the
information of the genotype/weight loss association studies published to date. In the future, the advance in
molecular genetic biotechnology will ease the way to combine the search for new candidate genes, novel
polymorphisms, and gene expression patterns putatively involved in gene-nutrient interaction concerning
weight homeostasis given the complexity of weight loss responses. Indeed, it is envisaged that the different
genotype-dependent responses to diets will contribute to develop personalized nutrition based upon the
genetic make up.
119
10:45
Session 2
11:15
NUTRICIÓN, LÍPIDOS Y ATEROSCLEROSIS / NUTRITION, LIPIDS AND
ATHEROSCLEROSIS II
Moderador / Chairperson: Jesús Millán. President Spanish Atherosclerosis Society
Dariush Mozaffarian
Department of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA, USA
Ácidos grasos trans, salud cardiovascular e implicaciones normativas / Trans fatty
acids, cardiovascular health, and policy implications
Consumption of industrially produced transfatty acids (TFA) is associated with substantial risk of
coronary heart disease, and possibly diabetes and sudden cardiac death. TFA intake has adverse
effects on multiple lipid and nonlipid risk pathways, with an overall constellation of effects that is
unique among dietary fats. Both individual-level and policy-level initiatives to reduce the global
consumption of industrial TFA intake should be a priority.
(+ info)
11:45
José M. Ordovás
Nutrition and Genomics Laboratory, Tufts University, Boston, MA, USA. CNIC, Madrid, Spain.
Globalización del estilo de vida: ¿Demasiado rápido para la lenta adaptación del
genoma? / Globalization of lifestyle: Too fast for our low pace genome?
(+ info)
12:15
The new technological advance in genomic is allowing an increasingly deeper knowledge of our
genetic makeup including the interindividual differences in our genomes. The current estimates are
that human genomes contain about 10 million polymorphic sites that makes each one of us look,
act, age and respond different to outside stimuli, such as nutritional factors. Many of these
differences are random mutations, but others have been selected because of evolutionary
pressures to adapt to the environment. However, in the current process of globalization, some of
these polymorphisms could place individuals to a higher risk of chronic diseases. The identification
of these variants can be used to achieve better disease prevention and treatment.
Antonia Trichopoulou
Department of Hygiene and Epidemiology, University of Athens Medical School, Athens, Greece
Aceite de oliva, dieta mediterránea y salud / Olive oil, Mediterranean diet and health
(+ info)
12:45
The health promoting traditional Mediterranean diet reflects the eating habits of the populations in
the olive-growing areas of the Mediterranean region until the early 1960s. Olive oil forms the basis
for the preparation of the majority of Mediterranean recipes, while as a single food entity it has
beneficial health properties which have been associated with the longevity of the Mediterraneans.
Mechanisms of action involve its high monounsaturated fatty acids content and, probably, the
presence of antioxidants or other minor constituents of biological significance such us phenolic
compounds and squalene. The high nutritional value of olive oil, in conjunction to its cultural and
culinary dimensions, lay a promising foundation enabling its wide use at home, in mass catering
and in semi-industrial scale, in the producing areas as well as internationally.
Seminario 1
13:15
Ponente: Juan A. Gómez-Gerique
Factores de riesgo emergentes /
Emerging risk factors
14:15
Almuerzo / Lunch
Session 3
15:30
Seminario 2
Ponente : Miguel A. Rubio
Dieta y prevención de enfermedad coronaria /
Diet and CHD prevention
SOBRE LA PATOFISIOLOGÍA DEL METABOLISMO LIPÍDICO / ON LIPID METABOLISM
PATHOPHYSIOLOGY
Moderador / Chairperson: Rafael Carmena. Endocrinology and Nutrition Service, Hospital Clinico
of Valencia, Spain
Patricio López-Jaramillo
Research Institute, Fundación Cardiovascular de Colombia, Floridablanca, Santander, Colombia
Enfermedades cardiometabólicas: papel de la programación fetal en respuesta a la
desnutrición materna / Cardiometabolic diseases: role of fetal programming as a
response to mother’s undernutrition
(+ info)
In Latin America, there is a high level of susceptibility to the development of insulin resistance and
low-grade inflammation at relatively low levels of abdominal obesity. This susceptibility is
associated with the adaptive response of the fetus to deficient fetal nutririon, which results in a
loss of anatomical structures such as nephrons, cardiomyocytes and pancreatic beta cells. These
adaptations may prove detrimental if food becomes abundant again after birth.
The high prevalence of maternal and fetal malnutrition could mean that the resulting fetal
adaptations may contribute to an increased risk of cardiometabolic disease.
16:00
John D. Brunzel
Division of Metabolism, Endocrinology and Nutrition, University of Washington School of Medicine,
Seattle, WA, USA
Hiperlipemia Familiar Combinada: Fenotipo y Genotipo / Familial Combined
Hyperlipidemia: Phenotype and Genotype
Familial Combined Hyperlipidemia (FCHL) is an oligogenic disorder which causes 15-20% of
premature coronary disease. Variable lipoprotein phenotypes occur in families and in a single
person. ApoB is always elevated and small-dense LDL present. One genetic locus relates to the
elevation of apoB, which is neither the apoB nor the LDL receptor genes. The lipid locus has been
associated with the genes for lipoprotein lipase, USF1, and the apoAI, CII, AIV, AV locus.
(+ info)
16:30
M. John Chapman
Dyslipidemia and Atherosclerosis Research Unit. INSERM (U. 551), Hôpital de la Pitié, Paris, France
Estructura de HDL, metabolismo y función: enfoque sobre la HDL3 densa / HDL
structure, metabolism and function: Spotlight on dense HDL3
(+ info)
17:00
The complex intravascular metabolism of HDL underlies their structural and functional
heterogeneity. The anti-inflammatory and anti-oxidative activities of HDL particles are highly
relevant to their atheroprotective action. Among the major HDL particle subpopulations, small
dense HDL3 exhibit the most potent anti-oxidative activity on a per particle basis. Significantly, the
proteome of dense HDL3 is distinct from that of other HDL subpopulations, and is a major
determinant of its anti-oxidative activity.
These studies support the contention that the metabolism, structure and function of HDL particles
are intimately related.
- Lilly Foundation Distinguished Career Award Ceremony -
17:30
VIERNES/ Friday, November /6th
08:15
Seminario 1
Seminario 2
Factores de riesgo emergentes /
Emerging risk factors
Dieta y prevención de enfermedad coronaria /
Diet and CHD prevention
Session 4
SOBRE LA PATOFISIOLOGÍA DE LA ENFERMEDAD CORONARIA / ON CORONARY HEART
DISEASE PATHOPHYSIOLOGY
Moderador / Chairperson: Pedro González-Santos. Internal Medicine Service, Hospital Clinico of
Malaga, Spain
09:15
Jesús Araujo
Division of Cardiology, Environmental Cardiology, David Geffen School of Medicine. Los Angeles,
CA, USA
Nuevo enfoque: Partículas contaminantes del aire, estrés oxidativo sistémico y
aterosclerosis / New focus: Air particulate pollutants, systemic oxidative stress and
atherosclerosis
(+ info)
09:45
Diseases of the heart are responsible for the first cause of death in the western world. Over the
recent years, cumulative epidemiological and experimental data have shown that exposure to air
pollutants lead to increased cardiovascular ischemic events and enhanced atherogenesis. It
appears that these associations are much stronger with the air particulate matter (PM) component
and that in urban areas, the smaller particles could be more pathogenic, as a result of their greater
propensity to induce systemic prooxidant and proinflammatory effects leading to the development
of dysfunctional HDL and promotion of atherosclerosis.
Emanuele Di Angelantonio
Department of Public Health and Primary Care, University of Cambridge, UK
La evidencia epidemiológica a gran escala colabora a evaluar los biomarcadores en
enfermedad cardiovascular / Using large-scale epidemiological evidence to help
evaluate biomarkers in cardiovascular disease
(+ info)
Until recently, the potential relevance of genetic, biochemical and lifestyle factors to coronary heart
disease have been studied in relative isolation from one another. Although this approach has
yielded some major insights, it has resulted in a fragmented and incomplete understanding of the
relative importance and interplay of nature and nurture in the development of coronary risk. This
talk provides a critical review of the strengths and limitations of established and emerging
epidemiological approaches to the study of the separate and combined effects of genetic,
biochemical and lifestyle factors in coronary heart disease.
121
10:00
10:40
Marja-Riitta Taskinen
Helsinki University Hospital, Helsinki, Finland
Anomalías de las lipoproteínas ricas en triglicéridos (TRLs) en la Diabetes tipo 2 y la
Resistencia insulínica / Abnormalities of triglyceride rich lipoproteins (TRLs) in Type 2
diabetes and insulin resistance
(+ info)
11:10
Both insulin resistance and Type 2 diabetes are characterized by dyslipidemia which is a common
and important CVD risk factor. Diabetic dyslipdemia is a cluster of potentially atherogenic lipid and
lipoprotein abnormalities that are metabolically interrelated. A fundamental defect seems to be an
overproduction of large VLDL particles which initiates a sequence of lipoprotein changes resulting
in higher levels of remnant particles, smaller LDLs and lower levels of HDL particles. Substantial
evidence support the concept that overproduction of large VLDL particles is driven by increased
liver fat content in man. We also reported that insulin fails to suppress VLDL production in subjects
with high liver fat volume. Thus, hepatic insulin resistance seems to cover also pathways of lipid
metabolism in the liver.
Peter Arner
Department of Medicine at Karolinska Institute, Huddinge University Hospital, Sweden
Celularidad del tejido adipose como factor novedoso de riesgo para el Síndrome
Metabólico y la enfermedad cardiovascular / Adipose tissue cellularity as a novel risk
factor for Metabolic Syndrome and CV risk
(+ info)
11:40
Session 5
12:10
Recent studies suggest that adult human adipose tissue is in a highly dynamic state. There is
marked ongoing adipogenesis and cell death leading to that 10% of the fat cell population is
renewed every year. This may influence the cellularity of adipose tissue so that some subjects
develop a hyperplastic adipose tissue (many small fat cells) and others a hyperthrophic adipose
tissue (few large fat cells). Adipose hyperthrophy is linked to type 2 diabetes, hypertension, insulin
resistance and dyslipidemia. Thus the turnover of human fat cells may be an important factor in
the development of metabolic syndrome and CV risk.
LAB-TECH Y AVANCES TERAPÉUTICOS EN LAS ENFERMEDADES CARDIOVASCULARES /
LAB-TECH & THERAPY ADVANCES IN CARDIOVASCULAR DISEASE
Moderador / Chairperson: Vicente Bertomeu. Cardiology / Hypertension Service, Universitary
Hospital Sant Joan d'Alacant, Alicante, Spain
Carlos Macaya
Instituto Cardiovascular, Hospital Clínico San Carlos, Madrid, Spain
Nuevos avances en cardiología intervencionista / New advances in interventional
cardiology
(+ info)
12:40
“Interventional cardiology”, a branch of cardiology that dates back to the 80´s, has undergone
whirlwind evolution in all cardiovascular disease, from heart disease to valve disease. The most
relevant advances in the last two years have been: 1) percutaneous implantation of valve
prostheses, and of mitral valve repair; 2) the development of new cardiovascular imaging
techniques such as optical coherence tomography (OCT) and spectral analysis of ultrasound signals
provide new information on the pathophysiology of arteriosclerosis, permitting us to discover the
composition of arteriosclerotic plaque (virtual histology) and providing a better therapeutic
approach; 3) finally, the new biodegradable stents have been shown to have a better biological
response following implantation and therefore give us reasonable hope that they will become the
treatment of choice in the not-so-distant future.
Guy De Backer
Gent University, University Hospital, Gent, Belgium
Eficacia y beneficios de la terapia farmacológica hipolipemiante. Las nuevas Guías
Europeas para la prevención cardiovascular / Efficacy and benefits of lipid-lowering drug
therapy. The new European Guidelines for cardiovascular disease prevention
(+ info)
Cardiovascular disease (CVD) can be prevented by intervening on the major modifiable risk
factors such as smoking, elevated blood pressure and elevated total or LDL cholesterol.
All guidelines on CVD prevention recommend to adjust the intensity of preventive actions in
accordance with the total CV risk of the individual. In the most recent guidelines of he 4th Joint
European Societies’ Task Force the use of non-pharmacological approaches are considered as the
cornerstone in all circumstances : no smoking, taking sufficient exercise and a healthy diet.
In the general population the goal is to keep them at low CV risk ; for total and LDL cholesterol the
targets are respectively < 5 and < 3 mmol/l. In those at high risk and in particular in patients with
established CVD , with diabetes type 2 or type 1 with microalbuminuria or with severe
hyperlipidaemia the aim is to reduce total cholesterol to < 4.5 mmol/l or < 4 mmol/l if feasible and
LDL cholesterol to < 2.5 mmol/l or < 2 mmol/l if feasible.
13:10
CONFERENCIA DE CLAUSURA / CLOSURE CONFERENCE
Moderador / Chairperson: José A. Gutiérrez-Fuentes. Fundación Lilly, Madrid, Spain
13:30
Seppo Ylä-Herttuala
A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular
Medicine, University of Kuopio, Finland
Epigenética y aterosclerosis / Epigenetics and atherosclerosis
Epigenetic mechanisms modify expression of many important genes involved in the pathogenesis
of atherosclerosis. It appears that both endogenous and exogenous factors can have direct and
relatively rapid effects on genomic function via methylation of DNA and methylation and
acetylation of histones. It is likely that better understanding of these mechanisms will lead to new
possibilities for the treatment of several chronic diseases, including atherosclerosis-related
diseases.
(+ info)
14:10
14:15
Almuerzo / Lunch
SEMINARIOS
Seminario 1
Factores de riesgo emergentes / Emerging risk factors
(+ info)
Seminario 2
Existen una serie de marcadores que han demostrado que pueden añadir valor en la estimación
individual del riesgo cardiovascular; si bien la lista es relativamente extensa, solo unos pocos han
sido validados e incorporados en alguna recomendación científica sobre su uso. Este es el caso de
la lipoproteína (a) (valor de decisión: superior a 30 mg/dl), Homocisteina (valor de decisión:
superior a 12 microgramos/L) y la cPCR (valor de decisión: superior a 3 mg/L). Si dos de estos
marcadores son “positivos” (magnitud superior al valor de decisión), se considera que el nivel de
riesgo estimado debe aumentarse un escalón sobre el obtenido con los factores de riesgo
convencionales.
Dieta y prevención de enfermedad coronaria / Diet and CHD prevention
(+ info)
Revisión del papel de patrones alimentarios, alimentos y nutrientes en el desarrollo de
las enfermedades cardiovasculares, más allá de la teoría lipídica clásica. Se hace una
puesta al día de la calidad de la grasa alimentaria, pero también con atención particular
a nutrientes capaces de modular la inflamación y el síndrome metabólico (carga
glucémica, papel de la fructosa) así como el papel de los flavonoides y otros
antioxidantes, de la suplementación vitamínica, esteroles vegetales, soja y otros
alimentos funcionales.
− Conferencias: 30-minute talks; 30-minute discussion after each session.
− English <> Spanish simultaneous translation.
− Seminarios: Dirigidos a la discusión y orientación de aspectos prácticos relacionados con la prevención, el diagnóstico
y el tratamiento, en grupos reducidos. Sólo español / Only spanish
Carlos Macaya, Jesús Millán, Juan A. Gómez-Gerique, Miguel A.
Rubio, Agustín Gómez de la Cámara, José A. Gutiérrez-Fuentes
EUROFORUM INFANTES
SAN LORENZO DE EL ESCORIAL, MADRID
Fundación Lilly
C/ María de Molina 3, 1º – 28006 Madrid – 91 781 50 70 - Fax 91 781 50 79 –
Secretaría y apoyo logístico
Ana Isabel Moreno - Grupo 7 Viajes (c/ Medea 4, 3º A - 28037 Madrid)
123
Las enfermedades del sistema nervioso ocasionan más del 20% del gasto sanitario en los países desarrollados, y es muy
posible que esta proporción aumente en el futuro. Es interesante resaltar que el SNC representa alrededor de un 20% del
metabolismo del cuerpo humano. Según los cálculos de la Organización Mundial de la Salud sobre la carga que suponen
las enfermedades medida en DALY’s, el 9% corresponde a las enfermedades mentales, el 1,7% a las enfermedades
cerebrovasculares, y el 34% a problemas del comportamiento. En total, puede decirse que alrededor del 45% de la carga
de las enfermedades corresponde al comportamiento o al órgano que lo regula. Además, entre las 10 enfermedades con
mayor carga, 5 son trastornos mentales.
De estos hechos, solo cabe deducir que las enfermedades del sistema nervioso son un reto sanitario de primera
magnitud y que la investigación en el ámbito de la neurociencia tiene ante sí la gran tarea de conseguir aumentar los
conocimientos necesarios para hacer frente a estas enfermedades.
Al mismo tiempo, la neurociencia tiene otro reto, al menos tan importante como aquel, que es el de conocer el
funcionamiento del sistema nervioso, en todo lo relacionado con nuestra actividad psíquica y con lo que nos caracteriza
como seres humanos conscientes, tanto a nivel individual como al nivel de especie. En ella, la combinación de
perspectivas clínicas y básicas ha demostrado ser un camino fructífero y apasionante. Por vez primera, empezamos a
atisbar la posibilidad de conocer lo que durante siglos han sido los sueños de filósofos y pensadores y, en el fondo, la
inquietud de cualquier ser humano.
investigación del sistema nervioso puede dar ante el reto de enfermedades tan discapacitantes y frecuentes como la
depresión y el síndrome bipolar, algunas de las cuales han sido causa de temores y estigmas muy extendidos a lo largo
de los siglos, y que han tenido su origen en la ignorancia y los prejuicios
“DESDE LA NEUROBIOLOGÍA A LA NOSOLOGÍA DE LAS ENFERMEDADES
MENTALES”
 Presidido por Juan José López Ibor.
 Celebrado en el Pabellón San Carlos. Hospital Clínico de Madrid.
 Fecha: 11 y 12 de marzo de 2010.
Durante el Simposio y a propuesta de la Sociedad Española de Psiquiatría, se hizo entrega del Premio:
Distinguished Career Award “Neuroscience/Psychiatry 2010”, a la Profesora Carmen Leal
"Desde la neurobiología a la nosología de las enfermedades mentales". Monográfico del 17º
Simposio Científico, editado en "Actas Españolas de Psiquiatría”. Volumen 38, Suplemento 3,
(ISSN: 1139-9287). Diciembre de 2010.
-
-
125
-PROGRAMA-
Directores / Chairmen: Juan José López-Ibor, Steven Paul
Lugar / Place: Auditorio del Hospital Clínico San Carlos, Madrid
Fecha / Date: March 11 & 12th, 2010
Jueves, 11 / Thursday, November / 11th
08:15
08:45
Por qué este Simposio / Why this Symposium
Session 1
09:00
DESAFIOS ACTUALES DE LA NOSOLOGÍA PSIQUIÁTRICA / ACTUAL CHALLENGES
OF PSYCHIATRIC NOSOLOGY
Moderador / Chairperson: Jerónimo Saiz Ruiz. Psychiatry Service, University Hospital
Ramon y Cajal. Madrid, Spain
Norman Sartorius
Association for the Improvement of Mental Health Programmes. Geneva, Switzerland
La clasificación de las enfermedades mentales: retos y recompensas / The
classification of mental disorders: challenges and rewards
(+ info)
09:40
Work on the revision of the International Classification of Diseases’ (ICD) 10th revision as
well as on the revision of the DSM-IV has begun. The World Health Organization as well as
the American Psychiatric Association have established structures that should help them to
produce proposals for the mental disorders chapter of the ICD-11 and the fifth revision of
the DSM a number of challenges stand before the two organisations as well as before other
organisations that are likely to initiate work on the revision of their own classifications.
These will be discussed as well as the potential gains of harmonization of classifications in
the field of mental health.
Juan J López-Ibor
Complutense University of Madrid, Hospital Clínicio San Carlos. Madrid, Spain
Los límites de la depresión / The limits of Depression
(+ info)
10:20
La discusión sobre lo que son estados normales y patológicos en el contexto de lo que hoy
se llaman trastornos del humor es antiguo y no ha tenido nunca soluciones satisfactorias. La
confusión empieza por la propia terminología general (sentimientos, afectos, emociones), la
propia terminología y de cada uno de los estados (tristeza, depresión, pesadumbre,
nostalgia, etc.). El hecho que los estados de ánimo responden a vivencias y a
acontecimientos externos complica aún más esta diferenciación. Las repercusiones son muy
importantes en la práctica de la medicina en lo que se refiere al diagnóstico y sus
consecuencias y a tratamientos. Para resolver el problema es necesaria primero una mejor
definición del ámbito de la vida sentimental y en segundo lugar, de cuáles son sus
componentes y en tercer lugar de qué función cumplen en el individuo y en la especia desde
un punto de vista adaptativo. Se trata de hacer una propuesta de diferenciación entre
depresiones mórbidas y estados emocionales negativos basados en su capacidad adaptativa
o desadaptativa.
Hagop S Akiskal
International Mood Center, University of California at San Diego, La Jolla, California, USA
Emoción, afecto y humor en la adaptación y la enfermedad / Emotion, affect,
mood in adaption and disease
Professor Akiskal has pioneered in the study of outpatient mood disorders. At the University
of Tennessee, he established mood clinics which have had worldwide appeal because of his
philosophy of conducting clinical training and research while delivering high quality care. His
clinical expertise ranges from dysthymia to bipolar spectrum disorders, as well as
comorbidity, resistant depression, interface of personality with mood disorders, mixed
states, anxious bipolarity, and PTSD.
(+ info)
11:00
127
11:30
Session 2
12:00
BASES NEUROBIOLÓGICAS DE LOS TRASTORNOS PSIQUIÁTRICOS
/NEUROBIOLOGICAL BASIS OF PSYCHIATRIC DISORDERS
Moderador / Chairperson: Manuel Martín-Carrasco. Padre Menni Psychiatry Clinic,
Psychiatry Research Institute, Pamplona, Spain
Julio Sanjuán
Department of Medicine, Psychiatry. Faculty of Medicine. University of Valencia. Spain
Interacción genes/M. ambiente en psiquiatría: lecciones desde una
aproximación evolutiva / Gene Environmental - Interaction in Psychiatry:
lessons from an Evolutionary Approach
The general medical model explains that there are genetic and environmental risks and
protective factors in the etiology of any complex disease. The main idea supported by this
model is the existence of good and bad polymorphisms. We present a review of the
literature and some examples of our own empirical studies about this issue in psychiatry;
with special focus on the methodological problems of this medical model.
An alternative evolutionary approach is proposed in order to solve these limitations.
(+ info)
12:40
Christopher Ross
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore,
Maryland, USA
Biología de las enfermedades neuropsiquiátricas / Biology of Neuropsychiatric
Disorders
(+ info)
13:20
14:20
Session 3
15:40
Genetics and neurobiology are beginning to illuminate the biology of psychiatric diseases.
Neurodegenerative diseases can provide a model, with insights into dementia, Parkinson’s
disease, and triplet repeat disorders including Huntington’s disease. Genome-wide
association studies and other genetic techniques are identifying new candidate genes for
schizophrenia and bipolar disorder. Cell models, including iPS cells, and mouse models, may
elucidate pathogenesis. As additional genes are identified, an iterative process of genetic
and phenotypic nosological reclassification of psychiatric disorders can begin.
Understanding genetic causes, and development of genetic models, will facilitate the study
of the interaction of genes and environment, and the development of novel approaches to
rational therapeutics.
Seminario 1
Seminario 2
Ponente: Miguel Bernardo.
Esquizofrenia: de la nosología la
neurobiología
Ponentes: Juan Barcia y Tomás Ortiz.
Neuromodelación y Enfermedades Mentales
Almuerzo / Lunch
ASPECTOS CLÍNICOS Y NEUROBIOLÓGICOS DE LA ESQUIZOFRENIA / CLINICAL &
NEUROBIOLOGICAL ASPECTS OF SCHIZOPHRENIA
Moderador / Chairperson: Julio Bobes. Department of Medicine – Psychiatry Area,
University of Oviedo, Asturias, Spain
Silvana Galderisi
Department of Psychiatry, Medical School, University of Naples SUN, Naples, Italy
Esquizofrenia con déficit: revision de los aspectos clínicos, biológicos y
terapéuticos / Deficit schizophrenia: an overview of clinical, biological and
treatment aspects
(+ info)
The proposal that deficit schizophrenia is a separate disease is based on the evidence that
deficit and non deficit schizophrenia differ on dimensions typically used to distinguish
diseases: signs and symptoms, course of illness, pathophysiological correlates, risk and
etiological factors, and treatment response. It might be argued that the deficit group simply
has a more severe form of the same illness as non deficit schizophrenia. However, two
decades of research on deficit schizophrenia have failed to prove that it represents the
extreme end of a severity continuum, while some findings support the claim that it may be
a separate disease entity.
16:20
Robin M Murray
Institute of Psychiatry at the Maudsley Hospital, King's College London, London, UK
¿Qué nos enseñan las psicosis inducidas por drogas sobre la esquizofrenia? /
What do drug-induced psychoses tell us about schizophrenia?
(+info)
A great deal is known about drug-induced psychosis. Unfortunately this knowledge has not
been brought into our understanding of schizophrenia because these conditions were thought
to be quite separate from idiopathic schizophrenia. Now that we know that schizophrenia is
just a syndrome with multiple-risk factors we can regard the drugs which induce psychosis as
risk factors. The first model psychosis was that consequent upon LSD and this gave rise to
the serotonin hypothesis of schizophrenia. Subsequently study of the effects of
amphetamines gave rise to the dopamine hypothesis. In recent years methamphetamine
psychosis has reached epidemic proportions in certain Pacific countries and has been growing
in frequency in North America. The clinical picture shows a close resemblance to the positive
symptoms of schizophrenia. It appears to be a consequence of dopamine sensitization. The
effects of PCP and ketamine gave rise to the glutamate hypothesis which seems more
appropriate for negative than positive symptoms, Finally, a series of cohort studies have
produced evidence that regular use of cannabis increases the risk of schizophrenia in a dose
related manner. Current research addresses the question of whether this effect is mediated
by dopamine, or whether an endocannabinoid hypothesis of schizophrenia is worth pursuing.
17:00
17:20
Miguel Casas
Psychiatry Service, University Hospital Vall d'Hebron, Barcelona, Spain
Cannabis y esquizofrenia / Cannabis and Schizophrenia
(+info)
18:00
Cannabis consumption is increasing in adolescents and during the last few decades
Public Health Authorities have expressed concern and raised the alarm in response to
the spectacular increase of its abuse in psychotic patients throughout the developed
world. At present, four possible explanations are proposed for the association between
cannabis consumpion and psychosis, which are not mutually exclusive:
1. Cannabis causes psychoses. Cannabis is a sufficient cause of psychosis in
individuals who otherwise would not suffer from the disorder.
2. Cannabis facilitates psychosis. Cannabis use can precipitate psychosis in people
with a pre-existing vulnerability for developing schizophrenia and may accelerate the
development of this disorder earlier than in non-users.
3. Cannabis induces psychotic exacerbation only in patients with
schizophrenia. Cannabis use is a factor of bad prognosis because it worsens the
natural evolution of schizophrenia leading to more frequent relapses, exacerbations and
recurrences.
4. Schizophrenia rends patients more liable to use cannabis. Schizophrenia is a
risk factor for cannabis consumption. First, because schizophrenia diminishes the
ability to control impulses, leading to an abuse of all drugs, including cannabis, and
second, because the use of substances can correct specific psychotic simptomatology,
can improve negative symptoms and can reduce side effects secondary to treatment
(self-medication hypothesis).
Gerd Kempermann
Center for Regenerative Therapies Dresden, Technical University of Dresden, Dresden,
Germany
Relevancia funcional y regulación de la neurogénesis dependiente de la
actividad en el cerebro adulto / Functional relevance and activity-dependent
regulation of neurogenesis in the adult brain
(+info)
Adult hippocampal neurogenesis contributes to lifelong cellular plasticity of the
hippocampus and presumably allows important activty-dependent adaptation
processes. This mechanism is of relevance for numerous neuro-psychiatric disorders,
which involve the hippocampus. The presentation deals with the idea that physical
exercise and cognitive training can contribute to the brain’s ability to cope with this
kind of pathology.
129
Viernes, 12 / Friday, March /12th
08:30
Session 4
09:30
Seminario 1
Seminario 2
Ponente: Miguel Bernardo.
Esquizofrenia: de la nosología la
neurobiología
Neuromodelación y Enfermedades
Mentales
ASPECTOS NEUROBIOLÓGICOS DE LA DEPRESIÓN / NEUROBIOLOGICAL
ASPECTS OF DEPRESSION
Moderador / Chairperson: Antonio Bulbena Vilarrasa. Director, Psychiatric Attention
and Health Institute (IMAS), Barcelona, Spain
Francesc Artigas
Neurochemistry Service, IIBB - CSIC – IDIBAPS, Barcelona, Spain
Neurogénesis y cicuitos cerebrales relacionados con la respuesta antidepresiva /
Neurogenesis and brain circuits involved in antidepressant response
(+ info)
10:10
Hippocampal neurogénesis is thought to play a major role in the therapeutic effect of
current antidepressant drugs. However, the diversity of antidepressant symptoms
suggests the involvement of several brain areas. Data obtained in recent years suggests
that deep brain stimulation of a ventral region of the prefrontal cortex (Cg25) is able to
evoke a rapid antidepressant response in patients treated with –and not responding to- a
variety of antidepressant treatments. The presentation will review experimental data
suggesting the involvement of brain circuits in which the prefrontal cortex plays a major
role in antidepressant response.
Jim van Os
Department of Psychiatry and Neuropsychology Maastricht University, The Netherlands
Tecnología de evaluación momentánea en la depresión: acentuando lo positivo /
Momentary assessment technology in Depression: accentuating the positive
New research using Momentary Assessment Technology shows that that the experience of
Positive Emotions at moments of stress buffers to a large extent against negative affective
reactivity in the flow of daily life. In addition, genes that render subjects vulnerable to
depression are expressed in part as increases in negative affective reactivity to stress.
However, this process is not deterministic and can apparently be moderated when
subjects are able to co-experience higher levels of positive emotions alongside increases
of negative affect after stressful events.
(+ info)
10:50
Thomas Frodl
Clinical Neuroimaging at the Department of Psychiatry, Trinity College Dublin, Ireland
Cambios en el hipocampo y remisión / Hippocampus changes and Remission
Evidence has emerged in the past decade that major depression (MDD), particularly
recurrent MDD, is associated with small hippocampal volumes. The biological pathways
through which stress may be linked to MDD, the emergence of chronicity or treatment
resistance in MDD, and the association between MDD and memory problems may be at
least partially understood by dissecting the association with depression and changes in the
hippocampus. MDD must be re-conceived as a complex illness, associated with
morphological brain changes that are detectable before illness onset and which may be
modified by clinical and treatment variables.
(+ info)
11:30
Session 5
11:50
ASPECTOS CLÍNICOS Y TERAPÉUTICOS DE LA DEPRESIÓN / CLINICAL AND
THERAPEUTIC ASPECTS OF DEPRESSION
Moderador / Chairperson: Carmen Leal Cercos. Psychiatry Service, Hospital Clínico de
Valencia, Spain
Eduard Vieta
Psychiatry Service, Hospital Clinico de Barcelona, Barcelona, Spain
El pronóstico de la enfermedad bipolar / The prognosis of bipolar disorder
Bipolar disorder is a serious, common condition. In recent years, it has been shown that
most patients have a highly recurrent course that may end up with clinically relevant
cognitive impairment and psychosocial disability. To establish the prognosis of bipolar
illness the relevant variables are: age at onset, family history, clinical subtype, psychotic
features, mood congruency of psychosis, seasonality, suicidality, comorbidity, cycling
pattern and frequency, and cognitive functioning. Social factors are also important.
Treatment response and timing may effectively modulate outcome. Psychoeducation is
crucial for good prognosis.
(+ info)
12:30
Andrés Lozano
Department of Surgery, Division of Neurosurgery, University Health Network, University of
Toronto, Canada
Estimulación cerebral profunda para la depresión / Deep Brain Stimulation for
Depression
(+ info)
13:10
There is increasing evidence that depression is linked to abnormalities and the function of
circuits that regulate mood. These circuits are accessible and their activity can be
modulated by electrical stimulation. We have applied deep brain stimulation of the
subcallosal cingulate gyrus to modulate the activity of dysfunctional circuits. Stimulation
here produces strong changes in the activity of circuit and this is accompanied by
improvements in certain patients’ depression. The biological basis and consequences of
stimulation at this site require further evaluation.
Rene Hen
Columbia University Pharmacology, New York, NY, USA
Neurogénesis y respuesta a los antidepresivos / Neurogenesis and
Antidepressant response
(+ info)
Adult hippocampal neurogenesis is a unique form of plasticity that generates new neurons
in the dentate gyrus throughout life. Adult-born neurons have been implicated in both
cognitive functions and in mediating the behavioral effects of antidepressants. However,
it is not known whether stimulation of adult hippocampal neurogenesis is sufficient to
improve cognition and mood. We used an inducible genetic gain-of-function strategy to
cell autonomously augment adult neurogenesis. We show that mice in which the proapoptotic gene, Bax, is deleted specifically in adult progenitors have increased survival of
adult-born dentate granule neurons, exhibit enhanced neurogenesis-dependent synaptic
plasticity and discriminate between similar contexts more efficiently than controls. In
contrast, increasing the number of adult-born neurons did not produce an antidepressantlike behavioral response. Our findings suggest therefore that strategies designed to
specifically stimulate adult hippocampal neurogenesis are likely to have pro-cognitive
effects associated with improved pattern separation, but may not be sufficient to enhance
mood.
CONFERENCIA DE CLAUSURA / CLOSURE CONFERENCE
Moderador / Chairperson: Juan J López-Ibor
13:50
Francine Shapiro
EMDR Institute. Mental Research Institute, Palo Alto, California, USA
Mente humana, psicoterapia y EMDR / Human mind, psychotherapy and EMDR
Over the past decade, the rapid treatment effects of EMDR have provided neurophysiological and clinical researchers with a “window into the brain.” In addition to the
neurobiological changes, the rapid shifts in cognition, affect and somatic response reveal
consistent patterns of internal associative processes. Systematic evaluation has also
demonstrated that a wide variety of diagnoses are caused or exacerbated by unprocessed
memories. Hence, EMDR treatment directly addresses the physiologically stored memory
networks that underlie both psychological problems and mental health. A clinical tape will
illustrate the findings, and the implications will be explored.
(+ info)
14:30
131
14:45
Almuerzo / Lunch
SEMINARIOS
Seminario 1
Ponente: Miguel Bernardo
Esquizofrenia: de la nosología la neurobiología
(+ info)
Seminario 2
(+ info)
La esquizofrenia es una compleja enfermedad del cerebro, atribuible a una alteración
precoz del desarrollo cerebral con componente genético, que produce anomalías en la
circuitería cerebral y que se manifiesta clínicamente por graves alteraciones del
pensamiento, percepción, emociones y conducta. El futuro pasa necesariamente por la
investigación neurobiológica. El estudio de las bases genéticas, tanto como marcadores o
como causas, así como el uso de la neuroimagen asociado a la neuropsicológica, cimenta
el diagnóstico en datos empíricos y objetivos. La biología molecular abrirá el camino del
conocimiento de sus bases biológicas permitiendo a la larga el desarrollo de auténticos
fármacos anti-esquizofrenia con nuevos mecanismos de acción, vías de administración y
nuevas dianas terapéuticas haciendo especial énfasis en los síntomas negativos y en los
fármacos pro-cognitivos.
Neuromodelación y Enfermedades Mentales
Brain activity can be modulated by different means, ranging from
cognitive or sensorial stimulation to deep brain stimulation by
implanted electrodes. This can be applied to treat a variety of mental
disorders. This therapy can be monitored by imaging techniques
showing the topographical representation of cortical function, such as
positron emission tomography, functional magnetic resonance or
magnetoencephalography. Recently introduced high density
electroencephalography with source analysis is revealing itself as a
flexible, quick and precise technique. The application of these
techniques to diagnosis, guidance and monitoring of brain
neuromodulation by cognitive, tactile or deep brain stimulation for
psychiatric patients will be reviewed.
(+ info)
− Conferencias: 30-min. talks; 10-min. discussion after each talk.
− English <> Spanish simultaneous translation.
− Seminarios: Dirigidos a la discusión y orientación de aspectos prácticos relacionados con la prevención, el diagnóstico
y el tratamiento. (Grupos reducidos). Sólo español / Intended for the discussion and orientation of practical aspects
related with the prevention, diagnosis and treatment (limited groups) <<Only Spanish>>
Juan José López-Ibor, María Inés López-Ibor,
Inmaculada Gilaberte, José A. Gutiérrez-Fuentes
AUDITORIO SAN CARLOS, HOSPITAL CLÍNICO DE MADRID
Calle Profesor Martín Lagos s/n – 28040 - Madrid
Fundación Lilly
C/ María de Molina 3, 1º – 28006 Madrid – 91 781 50 70 - Fax 91 781 50 79 –
Secretaría y apoyo logístico
Ana Isabel Moreno - Grupo 7 Viajes (c/ Medea 4, 3º A - 28037 Madrid)
La microbiota intestinal desempeña una función primordial en la nutrición, el desarrollo, el metabolismo, la resistencia a
patógenos, las respuestas inmunológicas y probablemente en muchas otras funciones importantes. Al igual que
cualquier órgano, la microbiota constituye un sistema altamente complejo sometido a la homeostasis interna y externa
del huésped. Esta microbiota es tan grande como otros órganos humanos y mucho más compleja en términos de
diversidad celular. En el intestino humano hay cerca de 6.000 taxones bacterianos que representan cerca de 100 billones
de células. Hasta hace poco, tal complejidad ha representado un obstáculo para los avances en la comprensión de las
funciones fisiológicas, y por consiguiente potencialmente patológicas, de este órgano tan poco reconocido pero de
fundamental importancia del cuerpo humano. Los actuales avances en genómica y bioinformática abren nuevos
caminos para comprender la fisiología de la microbiota, y en particular, el análisis del microbioma resulta esencial en
dicha tarea. Estamos empezando a conocer y comprender dichos avances, y este es el momento para debatir, definir y
poner en común los nuevos conceptos. Al menos, hoy todos compartimos la certeza de que nosotros, los seres humanos,
no estamos constituidos únicamente por células humanas.
A menudo, la medicina ha ignorado a la ecología, centrando su interés únicamente en campos más cercanos como la
etiología, la patogenia o la epidemiología. Este 18º Simposio científico de la Fundación Lilly trata de corregir ese punto
de vista, haciendo hincapié en la responsabilidad de que médicos, microbiólogos clínicos, especialistas en enfermedades
infecciosas, funcionarios de la salud pública y responsables políticos deben centrar su interés y recursos en la
investigación de las causas y las consecuencias de la alteración del microbioma humano, su predicción, así como la
corrección, a su debido tiempo, de posibles acontecimientos indeseables.
Es el propósito de la Fundación Lilly (www.fundacionlilly.com), de conformidad con sus objetivos estatutarios, ayudar a
difundir estos conceptos, y estamos seguros de cumplir con nuestro objetivo gracias a las personalidades altamente
cualificadas que han aceptado nuestra invitación para contribuir con sus conocimientos e ideas en cada una de las
intervenciones programadas.
“MICROBIOMA: DESCUBRIENDO EL ÚLTIMO ÓRGANO DEL CUERPO HUMANO”
 Presidido por Fernando Baquero, Andrés Moya y César Nombela.
Durante el Simposio y a propuesta de la Sociedad Española de Biología Evolutiva y de la Sociedad Española de
Enfermedades Infecciosas y Microbiología Clínica, se hizo entrega del Premio: Distinguished Career Award
“Microbiology 2010”, al Profesor Fernando Baquero Mochales.
“Microbiome: Deciphering the last human body organ”. CMI Clinical Microbiology and
Infection, Volume 18, Supplement 4, July 2012. Guest Editors: Andrés Moya, Rafael Cantón y
Didier Raoult
-
-
133
-PROGRAMA-
Chairmen / Presidentes: Fernando Baquero, Andrés Moya & César Nombela
Place / Lugar: San Lorenzo de El Escorial, Madrid, Spain
Date / Fecha: November 18 & 19th, 2010
Jueves, 18 de Noviembre / Thursday 18th
08:00
Acreditaciones / Registration
08:15
Apertura y Bienvenida / Opening and Welcome address
Por qué este Simposio / Why this Symposium
Plenary Session 1
08:30
THE HUMAN MICROBIOME 1 / EL MICROBIOMA HUMANO 1
Chairperson / Moderador: Fernando Baquero
Rob Knight
Department of Chemistry and Biology, University of Colorado at Boulder. Colorado, USA
Spatially and temporally explicit studies of the human microbiome / Estudios
explícitos espaciales y temporales del microbioma humano
(+ info)
09:00
The human microbiome is unexpectedly dynamic. New methods for enriched descriptors of
community structure and function, machine learning techniques to resolve body sites or
pathophysiological states, and to connect these descriptors to variation over time and space
are thus urgently needed.
In this talk, I describe our recent research on methods for analyzing long, dense timeseries
and for analyzing spatially explicit data, allowing us to obtain a detailed picture of variation
in different human body habitats and correlated variation among these habitats. The results
underscore the importance of supervised classification approaches, dense sampling over a
variety of spatial and temporal scales, integration and visualization of multiscale and
multimodal data, perturbation experiments, and cross-species integration in understanding
the human microbiome.
Stanislav Dusko Ehrlich
National Institute of Agronomic Research (INRA), France
Human microbiome project MetaHIT (Metagenomics of the Human Intestinal
Tract) / Microbioma humano, el proyecto MetaHIT (metagenómica del tracto
intestinal humano)
(+info)
09:30
We have established an extensive catalog that contains 3.3 million nonredundant gut
microbial genes, derived from 576.7 Gb Illumina metagenomic sequence of the DNA
prepared from faecal samples of 124 individuals of the European origin. The sequencing and
the assembly was carried out BGI Shen Zhen, one of the MetaHIT partners. The gene set is
>150-fold larger than the human gene complement, contains an overwhelming majority of
the prevalent microbial genes present in the cohort and likely includes a large proportion of
the prevalent human intestinal microbial genes.
Soren J. Sorensen
Molecular Microbial Ecology Group, Department of Biology, University of Copenhagen,
Copenhagen, Denmark
Metambolomics - Expanding our knowledge on the pool of plasmid encoded traits in natural
environments using high throughput sequencing / Metabolómica – Aumentando nuestro
conocimiento en el conjunto de marcadores de plásmidos en ambientes naturales mediante
sistemas de secuenciación de alta rentabilidad
Our current knowledge of mobile genetic elements (MGEs), and in particular plasmids, has largely been
derived from plasmid genomes obtained through traditional strain cultivation or isolation procedures like
exogenous plasmid isolation. These methods, almost universally, involve the introduction of specific
chemical selection biases geared towards antimicrobial resistance or xenobiotic degradation and rarely
produce sufficient data to assess mobilome structure on a community-wide scale. Although efforts in
genome sequencing have contributed more than 2,000 plasmid genomes, the combined pool of MGEs in
nature thus remains largely unexplored.
(+ info)
10:00
Discussion General Topic 1 / Discusión
10:30
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Plenary Session 2
11:00
THE HUMAN MICROBIOME 2/ EL MICROBIOMA HUMANO 2
Chairperson / Moderador: César Nombela
Angela M. Marcobal
Department of Microbiology and Immunology, Stanford School of Medicine, CA, USA
Insight into infant intestinal microbiota assembly: Genomics, genetics and
gnotobiotics / Visión del ensamblaje de la microbiota intestinal en la infancia:
Genómica, genética y gnotobiótica
(+ info)
11:30
Humans are born with a sterile digestive tract, which undergoes a seemingly chaotic
process of colonization over the first year of life. Many variables likely contribute to this
colonization process including human milk oligosaccharides (HMOs), a diverse class of
carbohydrates in mother’s milk that are not digested by the infant. We have combined
transcriptomic, genetics, comparative genomics and MALDI-FTICR mass spectrometry
to pursue the mechanisms underlying the metabolism of HMOs by Bacteroides, a major
genera of bacteria found in infant and adult gut. Our results reveal that the adaptation
of Bacteroides to host intestinal mucus allows this group of bacteria to consume the
structurally similar HMOs. We show that differential assembly of the intestinal
microbiota in gnotobiotic mice influences susceptibility to rotavirus and can be
monitored using mass-spectrometry-based metabolomics.
Willem M. de Vos
Laboratory of Microbiology, Wageningen and Helsinki University, Wageningen, The
Netherlands
The role of intestinal microbiota and host-microbe interactions in health and
disease / Papel de la microbiota intestinal y las interacciones huésped-microbio
en la salud y la enfermedad
There is great interest in analyzing the human microbiota in health and disease. While
being dominated by studies addressing its composition, the functional analysis of the
intestinal microbiome is receiving increasing attention and is advanced by recent high
throughput and systems developments. These include a variety of meta-analyses
approaches but also in homine studies on the function and host impact of single food
components or bacterial strains. This presentation will summarize these with specific
attention for their potential to develop biomarkers for health and disease
(+ info)
12:00
M. Pilar Francino
Genomics and Health, Center for Public Health Research, Valencia, Spain. University of
California Merced, CA, USA
Metagenomics and development of the gut microbiota in infants /
Metagenómica y desarrollo de la microbiota intestinal en niños
Colonization of the gastrointestinal tract (GIT) of human infants with a suitable microbial
community is essential for numerous aspects of health, but the progression of events by
which this microbiota becomes established is poorly understood. Another important
attribute of the GIT microbiota is its potential role as reservoir of antibiotic resistances.
We are investigating by means of diverse metagenomic approaches several areas of
microbiota development in infants, including the deployment of functional capabilities at
the community level, the presence of antibiotic resistances and the population genetics of
the most abundant genera.
(+ info)
12:30
13:00
13:30
14:30
- Lilly Foundation Distinguished Career Award Ceremony Seminario 1
Seminario 2
Ponente: José Luis Martínez.
Dpto. Biotecnología Microbiana, Centro
Nacional de Biotecnología, CSIC.
Cantoblanco, Madrid, Spain
Metagenómica y antibioticos
/Metagenomics and antibiotics
Ponente: Miguel Gueimonde.
Instituto de Productos Lácteos de Asturias
(IPLA), CSIC.
Villaviciosa, Asturias, Spain
Metagenómica y probióticos
/Metagenomics and probiotics
Almuerzo / Lunch
Plenary Session 3
16:30
HUMAN MICROBIOME: COMPUTATION / MICROBIOMA HUMANO: COMPUTACIÓN
Chairperson / Moderador: Andrés Moya
Peer Bork
European Molecular Biology Laboratory, Heidelberg, Germany
Towards molecular markers for the human gut microbiome / Hacia los
marcadores moleculares para el microbioma intestinal humano
(+ info)
17:00
With the increasing number of metagenomics datasets representing gut microbiota from
various human individuals, correlations can be identified between individualmolecules,
pathways, species or genera and various properties of the human host. While an
unsupervised clustering of the gut metagenomes of many individuals reveals discrete
groupings, none these groups could be related to particular phenotype.
However, for all of the host properties studied (e.g. gender, nationality, age and body
mass index), correlate with individual phenotypes encouraging research towards
diagnostics and perhaps even prognostics for various diseases.
Ana Gutiérrez-Preciado
Computational Genomics Laboratory, Molecular Microbiology Department, Biotechnology
Institute, Universidad Nacional Autónoma de México (UNAM), Cuernavaca, Morelos,
México
Elucidating metabolic pathways and digging for genes of unknown function in
microbial communities: the riboswitch approach / Dilucidando las vías
metabólicas e indagando sobre genes de función desconocida en comunidades
microbianas: la aproximación riboswitch
(+info)
Current methodologies for gene function identification rely on sequence homology, which
might not be accurate in most cases. For instance, only 3% of today sequences are
annotated as a result of experimental evidence, and 25% of the sequences are wrongly
annotated. Other methodologies have been proposed increasing gene annotation
accuracy; nevertheless these are only efficient when the complete genome sequence is
present. Here we propose a new approach based on the identification of the regulatory
mechanism governing genes without function assigned.
17:30
Eric Bapteste
UMR. CNRS 7138, Université Pierre et Marie Curie, Paris, France
Microbiotic metagenomics and the genetic worlds / Metagenómica microbiótica
y los mundos genéticos
I will show how gene networks and genome networks can in principle help
studying genetic diversity and its evolution. I will use real examples based on
human microbiomes data as a case study.
(+info)
18:00
19:00
Concierto de Órgano en la Basílica / Organ Concert at El Escorial Monastery (30’)
Viernes, 19 / Friday, November /19th
08:15
Plenary Session 4
09:15
Seminario 1
Seminario 2
Ponente: José Luis Martínez.
Metagenómica y antibioticos
/Metagenomics and antibiotics
Ponente: Miguel Gueimonde.
Metagenómica y probióticos
/Metagenomics and probiotics
HUMAN MICROBIOME IN HEALTH AND DISEASE 1 / EL MICROBIOMA HUMANO EN LA
SALUD Y LA ENFERMEDAD 1
Chairperson / Moderador: Rafael Cantón
Andrés Moya
Research Unit on Genomics and Health CSISP-UVEG/ Instituto Cavanilles, Valencia,
Spain
Metagenomics of human microbiome: beyond 16S rDNA / Metagenómica del
microbioma humano: más allá del 16<s rDNA
(+ info)
Symbiosis is playing an important role in eukaryotic evolution, man included. Within an
evolutionary context, bacterial communities living in our body could be considered as
functional adaptive complexes. The functional perspective is important to account for the
high levels of variability that appears when body samples and individuals and analyzed
and compared. Community function is like an attractor in the microbiota landscape. In this
talk I present this work hypothesis and some supporting results on gut metagenomics and
metatranscriptomics.
137
09:45
Patrice D. Cani
Université Catholique de Louvain, Louvain Drug Research Institute, Unit of
Pharmacokinetics, Metabolism, Nutrition and Toxicology, Brussels, Belgium
Role of the Gut Microbiota in the Development of Metabolic Diseases associated
with Obesity: Impact of the Endocannabinoid System / Papel de la microbiota
intestinal en el desarrollo de enfermedades metabólicas asociadas a la obesidad:
Impacto del sistema endocanabinoide
(+ info)
10:15
Obesity is characterised by altered gut microbiota, low-grade inflammation, and increased
endocannabinoid (eCB) system tone; however, a clear connection between gut microbiota
and eCB signalling has yet to be confirmed. We have reported that gut microbiota
modulate the intestinal eCB system tone, which in turn regulates gut permeability and
plasma lipopolysaccharide (LPS) levels. The impact of the increased plasma LPS levels and
eCB system tone found in obesity on adipose tissue metabolism (e.g., differentiation and
lipogenesis) remains unknown. By interfering with the eCB system using a CB1 agonist and
antagonist in lean and obese mouse models, we found that the eCB system controls gut
permeability and adipogenesis. We also show both in vivo and ex vivo that LPS and eCB
system control adipose tissue metabolism. In conclusion, our data indicate that gut
microbiota determine adipose tissue physiology through LPS-eCB system regulatory loops
and may play critical roles in adipose tissue plasticity during obesity.
Paul O’Toole
Department Microbiology & Alimentary Pharmabiotic Centre, University College, Cork,
Ireland
Changes in the intestinal microbiota from adulthood through to old age /
Cambios en la microbiota intestinal desde la edad adulta a la vejez
(+ info)
Multiple recent studies using culture-independent methodologies have recently defined the
composition of the intestinal microbiota in healthy adults, and in a limited number of
disease states. The normal faecal microbiota of older subjects has been less well
characterized. The ELDERMET study in Ireland has demonstrated significant interindividual variability in the faecal microbiota of several hundred elderly subjects, stratified
over a number of community groups and health states. Differences in the major phylum
proportions and in the core microbiota between elderly subject and younger adults were
identified, presenting prospects for health improvement in older subjects.
10:45
11:15
Plenary Session 5
11:30
HUMAN MICROBIOME IN HEALTH AND DISEASE 2 / EL MICROBIOMA HUMANO EN LA
SALUD Y LA ENFERMEDAD 2
Chairperson / Moderador: Manuel Serrano Ríos
Alex Mira
Research Unit on Genomics and Health CSISP-UVEG/ Instituto Cavanilles, Valencia,
Spain
Metagenomics of Oral Microbiota / Metagenómica de la microbiota oral
(+ info)
12:00
We present the metagenome of the human oral cavity. Direct pyrosequencing of 8
samples with different oral health status produced 1 Gpb of sequence without the biases
imposed by PCR or cloning.
Analysis of the reads indicated that the oral cavity is functionally a different environment
from the gut. Individuals that had never suffered from dental caries did not have mutans
streptococci but displayed high recruitment of other species and showed an enriched
fraction of several functional categories, like genes for antimicrobial peptides and quorum
sensing. Several isolates belonging to these dominant genera in healthy individuals were
cultured and shown to inhibit the growth of cariogenic bacteria, suggesting the use of
these commensal bacterial strains as probiotics to promote oral health and prevent dental
caries.
Peter Mullany
Division of Microbial Diseases, UCL Eastman Dental Institute. London, UK
Tetracycline resistance genes from the oral metagenome / Genes de resistencia
a la tetraciclina del metagenoma oral
Up to half the species in the oral microbiota can not yet be cultivated; therefore our
knowledge of the contribution of this environment to the reservoir of antibiotic resistance
genes and mobile genetic elements is incomplete. In this talk I outline our progress in
identifying novel mobile genetic elements and antibiotic resistance genes from the oral
metagenome.
(+ info)
12:30
Volker Mai
Department of Microbiology and Cell Science, Emerging Pathogens Institute, University of
Florida, USA
Gut microbiota associated with colorectal cáncer risk / La microbiota intestinal
asociada con el riesgo de cáncer colo-rectal
(+ info)
13:00
We performed a nested case control study in human volunteers undergoing a screening
colonoscopy. Data on dietary habits and medical history, a fecal sample as well as multiple
colon biopsy samples were collected from 91 subjects. We analyzed microbiota
composition by 16S rNA sequencing in 30 individuals presenting with at least one polyp
and 30 age and gender matched controls. 16S rNA sequences covering the V2 region were
initially analyzed using the RDP pipeline, followed by MEGABLAST again Greengeenes and
UNIFRANC analysis. Clear differences in OUT’s and pattern were detected.
CLOSURE CONFERENCE / CONFERENCIA DE CLAUSURA
Chairperson / Moderador: José A. Gutiérrez-Fuentes. Fundación Lilly, Madrid, Spain
13:30
Fernando Baquero
Hospital Ramón y Cajal Biomedical Research Foundation, Madrid, Spain
Metagenomic epidemiology: A need for antimicrobial resistance control /
Epidemiología metagenómica: necesidad de controlar las resistencias
antimicrobianas
(+ info)
The conventional surveillance of antibiotic resistance is centered particular, mostly
pathogenic, bacterial species. This classic point of view was inherited from the time where
mutation was conceived as the main way of developing resistance. In our days it has
become evident that in most cases the emergence, maturation, and spread of antibiotic
resistance depends on horizontal gene transfer. As genes belongs and evolve in complex
systems that involve multiple species and various mobile genetic elements, the
evolutionary pathways should be predicted considering such complexity. We advocate for
the adoption of multi-layered metagenomic epidemiology for surveillance and control of
antibiotic resistance.
14:10
Farewell / Despedida
14:15
Almuerzo / Lunch
SEMINARIOS
Seminario 1
Ponente: José Luis Martínez. Dpto. Biotecnología Microbiana, Centro Nacional de
Biotecnología, CSIC. Cantoblanco, Madrid, Spain
Jueves 18, 13:30 h y Viernes 19, 08:15h
Metagenómica y antibioticos /Metagenomics and antibiotics
(+ info)
Seminario 2
The advent of high-throughput gene sequencing technologies has allowed an increasing
capability of exploring microbial diversity including non-culturable organisms. In this
regard, metagenomic techniques, in occasions linked to synthetic biology have
demonstrated to be particularly well suited for the search of novel antibiotic resistance
genes as well as for analyzing the effect of different anthropogenic inputs on the
emergence, evolution and spread of resistance in different ecosystems. Besides,
metagenomics is a useful methodology for searching, without the need of culturing, novel
biological activities in complex ecosystems.
Ponente: Miguel Gueimonde. Instituto de Productos Lácteos de Asturias (IPLA), CSIC.
Villaviciosa, Asturias, Spain
Jueves 18, 13:30 h y Viernes 19, 08:15h
Metagenómica y probióticos /Metagenomics and probiotics
(+ info)
The development of extensive sequencing methods allowed carrying out metagenomic
studies on the human gut microbiome. This has tremendously increased our knowledge on
gut microbiota composition and activity. Metagenomic techniques have allowed identifying
microbiota aberrancies related to different diseases. These aberrancies constitute targets
for the development of probiotics directed to correct them. Probiotics are extensively used
to modulate gut microbiota. Nevertheless, metagenomic studies on the effects of
probiotics are still very scarce. In the near future, the use of metagenomics promises to
expand our understanding of probiotic action.
139
• Lectures / Conferencias: 30-minute talk; 30-minute discussion after each session. The official conference
language is English. Simultaneous translation English <> Spanish will be provided at the auditorium.
Participants in need for this service should pick up the headphones before session begins. A valid identification
document should be provided and will be returned at drop off.
• Seminarios: Dirigidos a la discusión y orientación de aspectos prácticos (Grupos reducidos. Solo en español)
/ Intended for the discussion and orientation of practical aspects. (Reduced groups. Only Spanish)
COMITÉ CIENTÍFICO ORGANIZADOR
Fernando Baquero, César Nombela, Andrés Moya, José A.
Gutiérrez
ORGANIZACIÓN Y PATROCINIO
Yolanda Martín, Fundación Lilly - 629861416 –
[email protected]
SECRETARÍA
Ana Isabel Moreno, Grupo 7 Viajes - 670888085 [email protected]
EUROFORUM INFANTES, SAN LORENZO DE EL ESCORIAL, MADRID
INFORMACIÓN EN: www.fundacionlily.com ● +34 91 781 50 70 ● [email protected]
As indicated in the institutional WEB, “The International Year of Chemistry 2011 (IYC 2011) is a worldwide celebration of
the achievements of chemistry and its contributions to the well-being of humankind”. The goals of IYC2011 are to
increase the public appreciation of chemistry in meeting world needs, to encourage interest in chemistry among young
people, and to generate enthusiasm for the creative future of chemistry. The year 2011 will coincide with the 100th
anniversary of the Nobel Prize awarded to Madame Marie Curie—an opportunity to celebrate the contributions of
women to science. The year will also be the 100th anniversary of the founding of the International Association of
Chemical Societies, providing a chance to highlight the benefits of international scientific collaboration.
th
Lilly Foundation, which has previously devoted several symposia to chemistry, has integrated this year its 19 Scientific
Symposium into the general scenery of celebrations. It is a way to recognize that chemistry produces seminal
contributions to biomedicine, building some of the initial steps of the creation of every new drug.
Inventing and developing a new drug is a long, complex, costly and risky process that has few peers in the field of
industry. Historically, as its today, creation of a new drug rides much –although not only- over the wave of new synthetic
technologies. The new synthetic methods, by which scientists can create increasingly complex molecules, are often in the
basis of the new, and more efficient molecular entities recently developed. In addition, present miniaturization and
automation of testing techniques is driving forward a parallel effort in improvement of synthetic methodology.
As usually, the 19th Lilly Foundation Scientific Symposium, “ORGANIC SYNTHESIS IN THE INTERNATIONAL YEAR OF
CHEMISTRY”, mixes scientists with different views and cultures in their approach to creation of new molecules. From the
use of new approaches in Pd chemistry, to the chemistry of silver and gold catalyzed reactions, to the recognition of
complex structures and surfaces, to new approaches in catalysis. From purely medicinal chemistry directed to precisely
chosen targets to the total synthesis of natural products whatever complex could they be, or to the design of more
efficient and selective synthetic strategies. Equilibrium is intended through the programme between two philosophies:
one that takes from nature its inspiration, while the other uses new tools and processes which knowledge and
technology is putting in our hands, and in our labs. This combination of lectures should make, we hope, an exciting offer
about modern chemistry.
Moreover, as we did in previous Fundacion Lilly Scientific Symposia, a mixture of well established masters – this year we
specially congratulate Prof. E. Negishi- with young emerging specialists has been selected by the committee, in the
expectation that this will create an inspiring and unique atmosphere for all participants.
“SÍNTESIS ORGÁNICA EN EL AÑO INTERNACIONAL E LA QUÍMICA”
 Presidido por Julio Álvarez-Builla, Jesús Ezquerra y Antonio Echavarren.
Durante el Simposio y a propuesta de la a propuesta de la Real Sociedad Española de Química, se hizo entrega del
Premio: Distinguished Career Award “Chemistry 2011”, al Profesor José Barluenga Mur.
“Organic Synthesis in the International year of Chemistry". Monográfico del 19º Simposio
Científico. Diciembre 2010
-
los asistentes al Simposio. (3.500 ejemplares)
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141
-PROGRAMA-
Chairmen:
Julio Álvarez-Builla, Antonio Echavarren, Jesús Ezquerra
th
April 14 & 15 , 2011
th
Thursday, April /14
08:00
Registration
08:15
Opening and Welcome address
Why this Symposium
Opening Conference
08:30
Chairperson: Julio Álvarez-Builla
Organic Chemistry Department. Faculty of Pharmacy. Alcala de Henares University. Spain.
Ei-Ichi Negishi
H.C. Brown Laboratories of Chemistry, Purdue University, W Lafayette, Indiana, USA
"Magical Power of d-Block Transition Metals – Pd-Catalyzed Cross-Coupling and ZACA Reaction"
(+ info)
Plenary Session 1
09:30
Half a century ago, a wide range of possibilities for use of d-block transition metals as catalysts for organic
synthesis were recognized. These opportunities stem from mainly two fundamental properties of the d-block
transition metals: (1) simultaneous presence or availability of HOMO and LUMO orbitals; (2) ability to undergo
ready and reversible Redox processes under one-set of reaction conditions. These properties have led to the
development of a large number and widely ranging processes including critically important C–C bond formation
reactions proceeding through: (a) reduction elimination (ex. Pd-catalyzed cross-coupling), (b) carbometalation (ex.
ZACA reaction), and (c) migration insertion (ex. carbonylation including “oxo” process). In this lecture, a brief
discussion of the Pd-catalyzed cross-coupling (mostly Negishi coupling) will be followed by a more detailed
discussion of the Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction).
Chairperson: Jesús Ezquerra
Tohru Fukuyama
Laboratory of Synthetic Natural Products Chemistry. Graduate School of Pharmaceutical Sciences. University of
Tokio. Tokio, Japan
“Improved Total Synthesis of Ecteinascidin 743 a.k.a. Yondelis®”
Ecteinascidin 743 (ET-743), a structurally complex marine natural product isolated from the colonial tunicate
Ecteinascidia turbinate, has been shown to exhibit potent antitumor activities. Yondelis®, a commercial name of
ET-743, has recently been approved by European Commission for the treatment of soft tissue sarcoma as well as
relapsed platinum-sensitive ovarian cancer. Since ET-743 is scarcely available from the tunicate, PharmaMar, a part
of Zeltia Group, is supplying it by a >20-step synthesis from cyanosafracin B which in turn be produced by
fermentation. This lecture will discuss our recent, improved total synthesis of ET-743, featuring L-glutamic acid as
the only source of chirality.
(+ info)
10:15
Cristina Nevado
Organic Chemistry Institute. University of Zurich. Zurich, Switzerland
“Total Synthesis of Natural Products”
In the past years, transition metals have become a powerful tool to construct molecular complexity from readily
available starting materials. The use of late transition metal catalyzed reactions will be highlighted here in the
context of natural product synthesis. On the other hand, computational tools have become a suitable platform for
structure based drug design: in silico docking methods have aided the design of novel kinase inhibitors with
promising biological profile.
(+info)
11:00
Coffee
143
11:15
Ernest Giralt
Parc Cientific de Barcelona. University of Barcelona. Barcelona, Spain
“Molecular Recognition at Protein Surfaces”
Protein-protein interactions are usually mediated through large areas that have complementary shape and charge.
So, in our opinion, medium-size peptide compounds can be very appropriate candidates to modulate this kind of
interactions.
The design of protein-surface binders and, specially, the design of ligands able to bind tightly and selectively to
hydrophilic proteinsurface patches is a very challenging task. In our laboratory, these last years we have been
trying to get some insight in the principles
that govern these molecular recognition processes. Our results underscore the crucial role of flexibility in the
recognition of protein surfaces.
(+info)
12:00
Carmen Nájera
Institute of Organic Chemistry (ISO). University of Alicante. Alicante, Spain
“Silver versus Gold-catalyzed Reactions”
(+info)
12:45
We describe here our recent work about the scope and limitations of gold(I) versus silver(l) catalysis in several
type of reactions. In the intermolecular hydroaminations of unactivated alkenes and dienes and the intramolecular
hydroamination of conjugated acyclic N-substituted aminodienes. Representative allylic alcohols have been
aminated using
cationic gold(I) complexes or silver salts. Comparative studies about the enantioselective synthesis of highly
substituted prolines by 1,3- dipolar cycloadditon of azomethine ylides with dipolarophiles using chiral silver and
gold(I) complexes are also presented. This reaction has been applied to the synthesis of hepatitis C virus inhibitors
blocking the viral RNA-dependent RNA-polymerase.
Paul Knochel
Department of Chemistry. Ludwig-Maximilians-Universität. Munich, Germany
"Preparation and Reactions of Functionalized Organometallics"
Two general methods for the preparation of functionalized organometallics of Zn, Mg, Al, and B will be described.
The first involves a LiCI-mediated direct insertion of a metal (Zn,Al,Mg) into an organic halide.
The second method is based on a direct metalation of aromatic, heterocyclic, and olefinic substrates with LiCIsolubilized bases.
Applications to the performance of diastereoselective cross-couplings will be reported.
(+info)
13:30
14:00
Lunch
Plenary Session 2
16:00
Chairperson: Concepción Pedregal
Andreas Pfaltz
Department of Chemistry. University of Basel. Basel, Switzerland
“New catalysts and substrate classes for asymmetric hydrogenation”
Iridium complexes with chiral P,N ligands have considerably enhanced the scope of asymmetric hydrogenation.
The catalysts are readily prepared, air-stable and easy to handle. In contrast to rhodium and ruthenium
diphosphine complexes, they do not require a coordinating group near the C=C bond and, therefore, allow
highly enantioselective hydrogenations of a wide range of unfunctionalized tri- and even tetrasubstituted
alkenes. In addition, they have also been successfully used for the hydrogenation of various functionalized
olefins, heterocycles such as furans and indoles, and imines. In this lecture the special properties, the scope, and
new representatives of this class of catalysts, as well as recent applications in natural product synthesis will be
discussed.
(+ info)
16:45
Mathew Gaunt
Department of Chemistry. University of Cambridge. United Kingdom
“New copper-catalyzed reactions”
This lecture will describe our work towards the development of a general catalytic reaction platform for chemical
synthesis. Specifically it will deal with the new reactions between simple organic molecules and hypervalent iodine
compounds
(+ info)
17:30
Coffee
17:45
Melanie S. Sanford
Department of Chemistry. University of Michigan. Ann Arbor, Michigan, USA
“Catalyzed C-H Functionalization Reactions”
This lecture will discuss my group's development of new transition metal catalyzed reactions for the selective
functionalization of -carbon hydrogen bonds. The talk will focus on detailed mechanistic investigations as a key
driver for the development of new catalysts and new reactions in this area. In each case, mechanistic studies have
provided critical insights for the development of novel catalysts with improved activity and/or selectivity.
(+ info)
18:30
Barry M. Trost
Chemistry Department. Stanford University. Stanford, CA, USA
“A Challenge for Total Synthesis: Atom Economy”
(+ info)
The improvement of synthetic efficiency requires that the fundamental tools of synthesis, the reactions
themselves, become more efficient-i.e. more selective and more atom economic. The ideal reaction from the point
of view of stoichiometry is an addition wherein 100% of the mass of all starting materials converts into mass of the
product (assuming a quantitative yield) and anything else is needed only catalytically. Unfortunately, most
synthetically important reactions are not additions although several are such as the Diels-Alder and aldol
reactions. Increasing the repertoire of addition reactions will be outlined. Special attention will focus on the utility
of such new methodology in evolving more efficient synthetic strategies to complex bioactive natural products.
The chemistry focuses on ruthenium catalyzed processes. Maintaining the same oxidation level streamlines
synthetic strategy as well as be more atom economic. Redox isomerization is one approach to accomplish this task
and leads to new syntheses of oxygen and nitrogen heterocycles. The alkene-alkyne coupling has proven to be very
effective both inter- and intramolecularly. While ruthenium remains the major catalysts, complexes of other
metals also lead to interesting and unprecedented reactivity for atom economy. Among them, palladium
complexes have proven to be quite interesting. Using atom economic reactions also has led to novel strategic
insights into complex targets. A strategy for the synthesis of the amphidinolide, laulimalide, and bryostatin families
reveals the power of these concepts.
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Friday, April /15
Plenary Session 3
08:15
Chairperson: Antonio Echavarren
Institute of Chemical Research of Catalonia - ICIQ, Tarragona, Spain
Stephen L. Buchwald
Massachusetts Institute of Technology. Cambridge, MA, USA
“Advances in Palladium-Catalyzed Coupling Reactions”
(+ info)
09:00
Palladium-catalyzed cross-coupling reactions are an important technology in both industrial and academic
laboratories. This lecture will detail the development of our biarylphosphine-based catalyst systems that
overcome many of the challenges that still remain for this methodology. A rationale for the combination of
the high levels of activity and the selectivity that these catalysts manifest will be presented. The
development of a catalyst system that combines two ligands and manifests an increased level of generality,
relative to those with a single ligand, will also be discussed. In addition, the application of these catalysts for
the preparation of a number of classes of heterocycles will be escribed. A great deal of the lecture will focus
on the use of two new classes of Pd precatalysts. With these, generation of the desired LPd(0) catalysts can
be quickly and efficiently carried out. The application of the newest of these to Suzuki-Miyaura coupling
reactions will also be described.
Hisashi Yamamoto
Dept. of Chemistry. The University of Chicago. Chicago, IL, USA
“Designing Acid Catalysis for Asymmetric Synthesis”
New reagents and catalysts have unlimited potential for the future of organic synthesis. We have been
interested in Lewis and Brønsted acid catalysis for a number of years. In this lecture, I am going to focus on
several of these acid and related catalysts from the aspect of their molecular design and engineering.
Lewis and Brønsted acids can be utilized as more effective tools for chemical reactions by sophisticated
engineering such as “designer acids”. The one approach is the combination of super Brønsted acid and
super silyl group to establish a cascade reaction to generate polyketide molecules in a single step. This
successive aldol process is a completely new version of the classical aldol reaction and provides numerous
opportunities to flexible control the stereochemistry of the product molecule.
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145
09:45
Amir Hoveyda
Dept. of Chemistry, Merkert Chemistry Center. Boston College, Boston, MA, USA
“New Concepts and Catalysts for Stereoselective Olefin Synthesis”
Catalytic cross-metathesis of two different terminal alkenes, a reaction that generates only the easily
removable ethylene as the side-product, constitutes a remarkably attractive and efficient strategy for
synthesis of disubstituted alkenes. What renders the goal of a Z-selective CM process a particularly daunting
challenge is that in the case of the large majority of related reactions reported thus far, is that the
energetically favored E olefin products are formed either predominantly or exclusively.
(+ info)
In this lecture, the first examples of catalytic cross-metathesis reactions will be presented, affording two
classes of olefins with exceptional Z-selectivity (>90% Z). Transformations, promoted with stereogenic-atMo complexes furnish the thermodynamically less favored alkenes isomers. Through utilization of unique
structural attributes of these catalysts, levels of reactivity and selectivity that were previously entirely out of
reach can be easily achieved. The critical electronic and steric characteristics of the catalysts and origins of
high Z-selectivity and synthesis of molecules of significance to biology and medicine will be discussed.
11:15
Coffee
10:45
Ilan Marek
Schulich Faculty of Chemistry. Technion-Israel Institute of Technology. Haifa, Israel
“New Stereoselective Strategies in Synthesis”
The stereoselective synthesis of all-carbon quaternary stereogenic centers in acyclic system is one of the
major challenges in synthesis and therefore, many new elegant synthetic strategies were developed in the
past few years, mostly through asymmetric catalysis. We have recently considered a different approach to
prepare such stereogenic centers and our most recent results will be described in this lecture.
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Plenary Session 4
11:30
Chairperson: Nazario Martín
Organic Chemistry Department I. Complutense University of Madrid. Madrid, Spain
Pedro J. Pérez
Experimental Sciences Faculty. Chemistry and Material Sciences Department. University of Huelva, Huelva,
Spain
“Novel C-C, C-N and C-O bond forming reactions catalyzed by group 11 metals”
(+ info)
12:15
Copper and silver complexes have been found to promote the following novel transformations.
- A new route to oxazoles via a [3+2] cycloaddition reaction of terminal alkynes and acyl azides (JACS 2011,
133, 191).
- The reaction of a series of furans with PhINTs to provide quantitative formation of 1,2-dihydropyridines
(JACS 2010, 132, 4600).
- A highly regioselective aziridination of dien-ols as the first step in an alternative route for sphingosine
(ACIE 2010, 49, 7092).
Also, the catalytic functionalization of methane and conversion into ethyl propionate will be presented
(Science 2011, in press).
James Monn
LRL Discovery Chemistry Res-Lead Op, Eli Lilly, Indianapolis, USA
“Discovery and Development of mGlu2/3 Receptor Agonists for the Treatment of Schizophrenia”
Schizophrenia is a devastating,life-long psychiatric disorder,and there is clear need for new treatment
options. We have directed our research toward the identification of agonists acting selectively at
metabotropic glutamate mGlu2/3 receptor subtypes as a non-dopaminergic approach for the treatement of
this disease. Our preclinical investigations have led to the identification of the conformationally contrained
heterobicyclic amino acid LY404039 as a potent and selective mGlu2/3 agonist and its N-linked methionine
amide LY2140023 monohydrate as an effective prodrug for the oral delivery of this molecule in humans.
This lecture will highlight both preclinical and clinical aspects of our research program.
(+ info)
13:00
Closing Conference
Kyriacos Costas Nicolaou
University of California, San Diego. The Scripps Research Institute. La Jolla, CA, USA
“Maitotoxin: An Inspiration for Synthesis”
Discovered in the gut of the sturgeon fish Ctenochaetus striatus and produced by the dinoflagellate
Gambierilidus toxicus, maitotoxin enjoys a special status in the annals of natural products chemistry.
Indeed, this substance is the largest and most toxic secondary metabolite isolated and characterized to
date. Its diverse spectrum of biological properties and fascinating structure elicited strong interest from
scientists who recognize its importance as a unique biomolecule and inspiration for research in biology and
chemistry. Based primarily on NMR spectroscopic, spectrometric, and synthetic studies, the molecular
structure of maitotoxin was proposed in 1996. In 2006, the originally assigned structure of maitotoxin was
questioned, precipitating new challenge for structural elucidation and chemical synthesis. Synthetic
endeavors in the field benefited from strategies and technologies developed during campaigns to construct
some of the less complex neurotoxins of the latter-like polyether marine class, of which maitotoxin is the
most complex and the fragship member. This lecture will review the progress made in these laboratories
toward large domains of maitotoxin with emphasis on methodology development, strategy design,
structural elucidation, and biological evaluation.
(+ info)
Closure / Farewell
Julio Álvarez-Builla, Antonio Echavarren, Jesús Ezquerra & José A. Gutiérrez-Fuentes
13:45
14:00
Lunch
CHAIRMEN & CHAIRPERSONS
J. Álvarez-Builla
A. Echavarren
J. Ezquerra
J. A. Gutiérrez-
N. Martín León
C. Pedregal
•
•
Lectures: 30-minute talk; 15-minute discussion after each talk.
The official conference language is English.
Julio Álvarez-Builla, Antonio Echavarren, Jesús Ezquerra,
José A. Gutiérrez-Fuentes
SECRETARÍA
INFORMACIÓN
AUDITORIUM, SAN LORENZO DE EL ESCORIAL, MADRID
Yolanda Martín, Fundación Lilly - 629861416 – [email protected]
Ana Isabel Moreno, Grupo 7 Viajes - 670888085 – [email protected]
www.fundacionlily.com ● +34 91 781 50 70 ● [email protected]
147
En los EEUU el comité asesor del 2010 Dietary Guidelines for Americans, señala a la obesidad como “la mayor
amenaza para la salud pública”, y pone de relieve que “las recomendaciones dietéticas básicas no han variado
sustancialmente en los últimos 30 años...”, pero añade que “cada vez se ha hecho más difícil comer bien..” Y continúa,
“mientras no se cambie el entorno alimentario, a las personas les resultará muy difícil seguir las guías o
recomendaciones dietéticas..” En el Reino Unido, el UK Foresight Report envía un mensaje similar: “la obesidad es una
de las cargas del mundo moderno, en el que los alimentos de alto valor o densidad calórica resultan abundantes y las
tecnologías que ahorran trabajo (físico) proliferan...”. En este entorno, “el exceso ponderal perjudicial para la salud se
hace frecuente en relación con la elección individual de la dieta, el ejercicio dejado de practicar y el llamado estilo de
vida”. Nos enfrentamos, por tanto, a una red compleja de factores sociales y biológicos que nos hacen vulnerables a la
ganancia de peso, y ello hace que el objetivo deba orientarse a limitar el ambiente “obesogénico” en que vivimos
inmersos y al que estamos expuestos.
La obesidad, por su gran prevalencia y trascendencia sanitaria y social, interesa tanto a investigadores y
especialistas - sobre todo internistas, endocrinólogos y cardiólogos-, como a aquellos médicos e investigadores que
desean profundizar en su conocimiento. Que en esta enfermedad multifactorial juegan otros factores como los
condicionantes genéticos, y que las consecuencias deletéreas de la obesidad obedecen a complejas interacciones con
otras enfermedades, y a mecanismos asimismo complejos que explican el deterioro del paciente y la aparición de
complicaciones, es materia cada vez mejor conocida.
Junto con la obesidad, la diabetes supone una verdadera pandemia del siglo XXI que acarrea un riesgo cierto
de padecer otras enfermedades como las cardiovasculares, o incluso el cáncer. Es propósito de la Fundación Lilly
(www.fundacionlilly.com), en consonancia con sus objetivos estatutarios, colaborar al mejor conocimiento de estos
conceptos, y confiamos en lograrlo gracias al notable plantel de personalidades que han aceptado nuestra invitación a
compartir sus conocimientos e ideas en este 20º Simposio Científico de la Fundación Lilly.
“OBESIDAD HOY”
 Presidido por D. Manuel Serrano Ríos y D. José A. Gutiérrez Fuentes.
 Celebrado en el EUROFORUM de San Lorenzo de El Escorial de Madrid.
Durante el Simposio y a propuesta de la a propuesta de la Sociedad Española de Endocrinología y Nutrición y la
Sociedad Española para el Estudio de la Obesidad, se hizo entrega del Premio: Distinguished Career Award
“Endocrinología y Nutrición. Obesidad 2011”, a la Profesora Gema Frühbeck
“Obesity Today". Monográfico del 20º Simposio Científico. Editado en la Revista
ENDOCRINOLOGÍA Y NUTRICIÓN, Volumen 60, Monográfico 1, Febrero 2013. (ISSN:1575-0922)
-
Distribución: suscriptores de la revista Endocrinología y Nutrición y a los asistentes al
-
Estará disponible en formato pdf. en la página web de la Fundación.
149
Chairmen: MANUEL SERRANO-RIOS & JOSE A. GUTIERREZ-FUENTES
Venue: EUROFORUM Campus Infantes, San Lorenzo de El Escorial, Madrid
Date: November 24th & 25th, 2011
th
Thursday, November 24
08:00
Registration
08:20
Why this Symposium
Opening Conference
08:30
Chairperson: Manuel Serrano-Rios
Profesor Emérito de Medicina Universidad Complutense de Madrid Madrid, Spain
Jens C. Brüning
Institute for Genetics, University of Cologne. Max-Planck-Institute for Neurological Research, Cologne, Germany
“The brain, and the regulation and dysregulation of energy homeostasis: Its relevance to obesity”
(+info)
Session 1
09:10
The central nervous system (CNS) controls not only parameters of energy homeostasis i. e. food intake and energy
expenditure but also regulates peripheral glucose metabolism. Particularly, insulin action in the central nervous
system plays an important role in control of hepatic gluconeogenesis. Via control of specific neuronal populations in
the arcuate nucleus of the hypothalamus insulin regulates autonomic innervation of liver to ultimately fully suppress
hepatic glucose production. The presentation will focus on experiments using tissue-specific knockout and
transgenic mice to unravel the molecular basis of CNS control of hepatic glucose production and its dysregulation
upon obesity development.
OBESITY: GENERAL ASPECTS
Chairperson: Manuel Serrano-Rios
Philip T. James
International Obesity Task Force. London, UK
“Obesity: A modern pandemic. The burden of disease"
(+info)
09:40
The obesity epidemic was evident in lower income countries in 1995 and WHO had a special expert technical
meeting in 1997 highlighting the many problems associated with obesity. However, it was only when the analysis of
the global burden of diseases emerged after a major new exercise at the turn of the Millennium that it became
evident that excess weight gain was in the top 10 risk factors for all health problems on a global basis. Now it is
number three in the affluent world and modeling suggests that no country will be able to afford the economic
consequences of weight gain. This therefore is shifting governmental and medical thinking with radical new
proposals for developing more effective methods to both preventing excess weight gain and deal with the 1.5 billion
adults who already are suffering from overweight/ obesity with all its many consequences.
Luis Moreno-Aznar
Health Sciences University School. University of Zaragoza. Zaragoza, Spain
“Obesity in children-adolescents. A critical review"
Obesity in children and adolescents has a high prevalence in most countries worldwide. At this age obesity is
associated with a large number of complications and for this reason it represents a major public health problem.
Prevention programmes implemented to date have provided fairly unsatisfactory results and it is therefore
necessary to design more innovative programmes in the future.
(+info)
10:10
10:40
Coffee Break
Mark A. Hanson
Institute of Developmental Sciences, University of Southampton. Southampton, UK
“Developmental origins of obesity"
(+info)
Obesity is an over-increasing problem in both developed and developing societies, especially as the adoption of a
Western diet and sedentary lifestyle takes place. Despite many attempts to raise awareness of the problem, it
appears that current initiatives to prevent or reduce obesity are not working. They are largely focused on adults and
at preventing “gluttony and sloth”. Whilst some at risk individuals can lose weight, this is usually not substantial and
is hard to sustain. The intervention comes too late and does not take account of the processes in early life which
establish aspects of appetite, food and exercise preference and metabolic control. Such processes in pre- and early
post-natal life involve epigenetic effects on gene expression, in response to maternal (and perhaps paternal) cues
about the environment, and influence the developing phenotype of the offspring. Understanding such processes
could provide new early biomarkers of individuals at risk and suggest potential interventions and ways of monitoring
their effectiveness.
151
11:10
Jose-Alfredo Martinez
Dept. of Nutrition and Food Science Physiology and Toxicology, University of Navarra. Pamplona, Spain
“Epigenetics of obesity and weight loss"
It is becoming evident that interindividual differences concerning the outcomes of nutritionally-related chronic
diseases depend not only on the dietary intake and the subject’s DNA sequence, but also on the inherited
epigenome and on different nutritional influences (during the intrauterine or the adult periods) that modify the
epigenetic marks and are able to affect gene expression, which includes DNA methylation, covalent histone
modifications, chromatin folding and, more recently described, the regulatory action of miRNAs
(+info)
11:40
12:15
(only Spanish)
Discussion General Topics 1
Seminario 1
Ponente: Alfonso Calle-Pascual
- Tratamiento no farmacológico de la obesidad
13:15
Session 2
15:30
Seminario 2
Ponente: Miguel A. Rubio-Herrera
- Tratamiento farmacológico de la obesidad
Lunch
OBESITY: PHYSIOPATHOLOGY
Chairperson: Xavier Formiguera
Morbid Obesity Unit University Hospital Germans Trias i Pujol, Barcelona, Spain
Fredrik Karpe
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford. Oxford, UK
“Fat distribution, ectopic fat and non-alcoholic fatty liver disease"
Obesity increases the risk for diabetes, cardiovascular mortality and morbidity. However, the risk is strongly
associated with abdominal obesity there is suggestive epidemiological evidence to suggest that lower body fat
accumulation is protective. The talk will examine the possibility that different human fat depots have different
functional characteristics explaining these associations. In particular, gluteofemoral fat appears particularly effective
in trapping fatty acids for safe and long-term storage.
(+info)
16:00
Nathalie Delzenne
Drug Research Institute, Université Catholique de Louvain. Brussels, Belgium
“Role of nutrient-gut-microbiota interactions in human obesity, insulin resistance and type 2 diabetes"
Nutrients, such as arabinoxylans or fructans, can drive changes in the gut microbiota composition in favour of
beneficial bacteria such as bifidobacteria or roseburia, and are therefore called prebiotics . Prebiotics reduce obesity,
but also glycemia and hepatic insulin resistance in obese animals, namely by increasing the number of endocrine L
cells in the jejunum and in the colon Intervention studies in obese and diabetic patients are in progress to estimate
the relevance of microbial changes occurring upon prebiotics, but also targeted probiotics approaches on the
potential improvement of inflammation and glucose homeostasis associated with obesity.
(+info)
Pause
16:30
16:45
Gema Medina-Gomez
Dept. of Biochemistry, Physiology and Molecular Gentics, Faculty of Health Sciences, Rey Juan Carlos University.
Madrid, Spain
“Obesity and type 2 diabetes in the renal pathology"
Individuals with metabolic syndrome are also at increased risk for developing chronic kidney disease. However, it is
unknown what pathomechanisms are underlying the development of this renal injury. It is known that obesity and
diabetes causes glucolipotoxicity associated to increased glycemia and accumulation of reactive lipid species
affecting metabolically relevant organs different to adipose tissue. The roles of glucose and fatty acids as toxic
factors influencing kidney function and the aetiology of chronic kidney disease are debated.
(+info)
17:15
Dominique Langin
Laboratoire de Recherche sur les Obésités, INSERM U1048-I2MC, Equipe 4. Toulouse, France
“Adipose tissue lipolysis and insulin sensitivity "
(+info)
Fatty acids (FA) play a pivotal role in the genesis of insulin resistance. The mechanisms underlying the relation
between white adipose tissue (WAT) lipolysis and insulin sensitivity have been investigated in high fat diet-fed obese
mice haploinsufficient for hormone-sensitive lipase (HSL), one of the enzymes catalyzing degradation of
triacylglycerol into FA in WAT. Blunted lipolytic capacity is associated with reduction in FA turnover and
improvement of insulin sensitivity and glucose metabolism without modification of fat mass and WAT inflammation.
Treatment with a specific HSL inhibitor attenuates insulin resistance in high fat diet-fed mice. Insulin control on
glucose metabolism is improved by HSL gene silencing in human adipocytes. In vivo, a positive association is
observed between human WAT lipolytic rate and indexes of insulin resistance. A reduction in WAT lipolytic capacity
can reshape fatty acid fluxes and improve insulin sensitivity and glucose metabolism.
17:45
th
Friday, November 25
Seminario 1
08:30
(Only Spanish)
Sesión 3
09:30
Seminario 2
- Tratamiento no farmacológico de la obesidad
Ponente: Miguel A. Rubio-Herrera
- Tratamiento farmacológico de la obesidad
OBESITY: PREVENTION AND TREATMENT
Chairperson: José A. Gutiérrez-Fuentes
Fundación Lilly. Spain.
Gema Frühbeck
Metabolic Research Laboratory, Clinica Universitaria, University of Navarra. Pamplona, Spain
“The healthy weight debate: Does it apply to weight loss in obesity"
(+ info)
10:00
With the recognition of obesity as one of the major public health problems, refining the practicalities of its diagnosis
and management has jumped to a first-priority challenge. Strictly speaking, obesity is not defined as an excess of body
weight but as an increased adipose tissue accretion, to the extent that health may be adversely affected.
Since weight loss does not necessarily imply a decrease in body fat and more so in visceral adiposity, it is important to
go beyond the mere determination of body weight and BMI. Therefore, the body compartment that lies at the centre of
the development of most comorbidities and circulating biomarkers of cardiometabolic risk should attract our attention
regarding not only an accurate diagnosis, but also an adequate management and follow-up.
Aila Rissanen
Obesity Research Unit, Dept of Psychiatry, Helsinki University Central Hospital. Helsinki, Finland
“Preventative strategies for obesity: A critical appraisal”
(+ info)
The prevanlence of obesity is escalating worldwide, reflecting the inability of most societies to prevent the deleterious
rise of the epidemic. Efforts to halt/reverse the tide include o.a. (1) Improving dietary habits and increasing physical
activity in the population through information and media campaigns, promoting nutritional education at home, at
school and in the community, (2) Influencing the food industry to promote the production and distribution of healthier
products, (3) Activating health professionals in dealing with obesity and its prevention, (4) Constant monitoring of the
health (incl. obesity level) of the population.
Coffee Break
10:30
11:00
Felipe Casanueva
Dept. of Medicine, Service of Endocrinology and Nutrition, Hospital Clinico de Santiago de Compostela. Santiago de
Compostela, Spain
“Obesity and the future. New problems and new solutions "
The prevalence and incidence of obesity in the world and in Spain will be evaluated focusing in the extreme ends of
age. The rate of increase will be commented. Some of the complication induced by adiposity excess will be discussed,
among them the relationship with some types of cancer.
Some concepts of food intake regulation will be presented. Finally no-pharmacological and no-nutritional therapies will
be reviewed.
(+ info)
11:30
Antonio Torres-Garcia
International Federation for Surgery of Obesity. Servicio de Surgery, Hospital Clinico San Carlos. Madrid, Spain.
“Metabolic surgery for obesity: A critical account"
(+ info)
In the field of severe obesity, it is now widely accepted by the scientific community that surgery is undoubtedly the
therapeutic option that offers the best results. The outcome of surgical manipulation of the gastrointestinal tract in
patients with morbid obesity was reviewed and it was found that the different surgical approaches not only achieve
significant weight reduction and normalisation of body mass index (BMI), but also attain surprising control of the
metabolic comorbidities that accompany obesity: type 2 diabetes mellitus (DM 2), hypertension,
hypercholesterolaemia and hypertriglyceridemia. The importance of this finding is reflected in the fact that almost all
scientific societies have changed their names to Societies of Bariatric and METABOLIC Surgery.
Since then, the term METABOLIC SURGERY has come into widespread use and there has been a spurt of studies that
attempt to assess the metabolic outcomes of these different procedures.
This paper will discuss current results in the control of metabolic alterations related to excess weight and obesity:
diabetes mellitus, lipid metabolism disorders and hypertension. It will also address the most controversial aspects and
will analyse future expectations.
12:00
12:30
153
Closing Conference
Chairperson: José A. Gutiérrez-Fuentes
Fundación Lilly. Spain.
Antonio Vidal-Puig
University of Cambridge Metabolic Research Laboratories. Cambridge, UK
13:15
“Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome"
The link between obesity and type 2 diabetes is clear on an epidemiological level, however the mechanism linking these
two common disorders is not well defined. One hypothesis linking obesity to type 2 diabetes is the adipose tissue
expandability hypothesis. The adipose tissue expandability hypothesis states that a failure in the capacity for adipose
tissue expansion, rather than obesity per se is the key factor linking positive energy balance and type 2 diabetes. All
individuals possess a maximum capacity for adipose expansion which is determined by both genetic and environmental
factors. Once the adipose tissue expansion limit is reached, adipose tissue ceases to store energy efficiently and lipids
begin to accumulate in other tissues. Ectopic lipid accumulation in non-adipocyte cells causes lipotoxic insults including
insulin resistance, apoptosis and inflammation. This article discusses the links between adipokines, inflammation,
adipose tissue expandability and lipotoxicity. Finally, we will discuss how considering the concept of allostasis may
enable a better understanding of how diabetes develops and allow the rational design of new anti diabetic treatments.
(+ info)
Closure / Farewell
14:00
Manuel Serrano Ríos & José A. Gutiérrez-Fuentes
14:15
Almuerzo / Lunch
Xavier Formiguera, Manuel Serrano-Rios and Jose A. Gutierrez-Fuentes
SEMINARIOS
Seminario 1
Servicio de Endocrinología y Nutrición, Hospital Clínico San Carlos. Madrid, Spain
Tratamiento no farmacológico de la obesidad
(+ info)
Seminario 2
La obesidad representa un problema creciente y de primera magnitud en los países desarrollados asociado a un disbalance entre la energía ingerida con la alimentación y la gastada durante el ejercicio físico, y persiste siendo un
problema por resolver. Diferentes factores modificables se han asociado al incremento en el peso corporal. Pero la
intervención sobre dichos factores ha obtenido en general un resultado pobre.
El tratamiento de obesidad consiste en alcanzar la máxima reducción de ponderal que sea capaz de mantener a
largo plazo. La reducción en la densidad de los alimentos y en el tamaño de las porciones representa una de las
intervenciones de mayor eficacia. Diferentes estrategias encaminadas a incrementar el gasto calórico inducido por
el ejercicio físico habitual es un tratamiento que ayuda a mantener la pérdida de peso alcanzada. Intervenir sobre
la forma de comer en general tiene unos resultados pobres a largo plazo. En el taller se referirán las estrategias que
han mostrado ser más eficientes.
Unidad de Nutrición Clínica y Dietética, Hospital Clínico San Carlos. Madrid, Spain
Tratamiento farmacológico de la obesidad
Históricamente los tratamientos farmacológicos empleados en la obesidad se han ido retirando sucesivamente
cuando los beneficios no han superado a diferentes efectos secundarios (recientemente Sibutramina y
Rimonabant). Se repasará la situación actual de nuevas moléculas utilizadas en monoterapia (Lorcaserina, Cetilistat,
agonistas de GLP1) o en combinación (Qnexa, Contrave, entre otras). También se discutirá el papel de fármacos
como los ISRS y antiepilépticos en el manejo de conductas alimentarias anómalas.
(+ info)
INFORMATION
Conferences: 30-minute talk; 30-minute discussion after each session / English <> Spanish simultaneous translation
Seminarios: Intended for the discussion and orientation of practical aspects related with the prevention, diagnosis and treatment (limited groups. Only
Spanish)
Manuel Serrano-Ríos & José A Gutiérrez-Fuentes.
INFORMACIÓN EN: (+34) 91 781 50 70 ● [email protected]
Cancer is the commonest genetic disease. One in three people in the Western world develop cancer and one in five die
of the disease. All cancers arise due to alterations in DNA. Some cancer-causing mutations may be present in the
germline, are therefore heritable and confer an elevated risk of developing cancer. Many, however, occur over the
course of a person’s lifetime in individual cells of the body and are known as somatic mutations. Acquisition of
additional mutations, and consequent waves of clonal expansion result in the evolution of the mutinous cells that
invade surrounding tissues and metastasise.
Within each cancer genome, subsets of the somatic alterations are “driver” mutations in “cancer genes” which cause
the cancer to develop. The search for cancer genes and the “driver” mutations within them has been a central aim of
cancer research for 30 years and more than 300 genes have already been identified in which somatic alterations are
associated with cancer.
Since the advent of recombinant DNA technology, the identification of genes that are mutated and hence drive
oncogenesis has been a central aim of cancer research. The study of these “cancer genes” has generated most of our
biological insights into the process of oncogenesis. Cancer genes and the pathways in which they are involved have
been used successfully as the targets for the development of new therapeutic agents.
This is an ongoing strategy and we will be adding further data in the future. Establishing a complete catalogue of
somatic genetic changes in individual cancers will therefore reveal the full set of driver mutations and cancer genes that
are operative in each type of cancer.
It will also reveal the full set of passenger mutations and hence yield insights into underlying mutational processes,
including exposures and DNA repair defects. It is now possible to contemplate the complete cataloguing of genetic
alterations in different types of cancers, with the expectation that our current ability to classify tumors will be refined
and improved by classification according to the mutational profiles of each tumor. Combined with the development of
rational therapies on the basis of new understanding of the genomics of the individual cancers, many new therapeutic
opportunities will become available.
We are holding this 21st Fundacion Lilly Symposium for bringing together leading scientists and clinicians with
pharmaceutical companies, to approach the state of the art on Cancer Genomes knowledge, discuss candidate
mechanisms and predictors of drug resistance and therapeutic efficacy. We expect the discussion to foster the efforts
for integrating cancer research in the search of more efficient therapies.
“CANCER GENOMES: CLINICAL AND THERAPEUTICAL IMPLICATIONS”
 Presidido por D. Elías Campo, D. Carlos López-Otín y D. Mariano Barbacid.
 Celebrado en el EUROFORUM de San Lorenzo de El Escorial de Madrid.
Durante el Simposio y a propuesta de la Asociación Española de Investigación contra el Cáncer, se hizo entrega
del Premio: Distinguished Career Award “CANCER 2012”, al Profesor Ciril Rozman Borstnar.
155
Chairmen: CARLOS LÓPEZ-OTÍN, ELIAS CAMPO, MARIANO BARBACID
Venue: EUROFORUM Campus Infantes, San Lorenzo de El Escorial, Madrid
Date: November 22th & 23th, 2012
th
Thursday, November 22
07:45
Registration
08:00
Why this Symposium
Session 1
08:10
HUMAN GENOME AND EPIGENOME
Chairperson: Mariano Barbacid. Spanish National Cancer Research Centre. Madrid, Spain
Lou Staudt
National Cancer Institute. Bethesda, MD, USA
Therapeutic strategies in lymphoma from structural and functional genomics
The Staudt laboratory developed genomic-scale gene expression profiling to define the molecular basis of
therapeutic response and survival in lymphoid malignancies. This effort revealed that the most common
type of non Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), is actually comprised of three
pathogentically distinct diseases with different responses to current chemotherapy. To uncover new
therapeutic targets, the Staudt laboratory developed RNA interference genetic screens for essential genes
in cancer. Using this methodology, in conjunction with high throughput cancer gene resequencing, the
laboratory identified the NF-kB, B cell receptor and MYD88 signaling pathways as therapeutic targets for
the ABC subtypes of DLBCL, which is least curable by current treatments. Clinical trials are underway in
relapsed/refractory DLBCL of ibrutinib, a small molecule inhibitor of the kinase BTK in the B cell receptor
signaling pathway. A high frequency of complete and partial responses to ibrutinib have been observed in
ABC DLBCL, consistent with the reliance of this lymphoma subtype on chronic active B cell receptor
signaling.
08:50
Roderic Guigo
Centre for Genomic Regulation (CRG). Barcelona, Spain
Redefening RNA in the ENCODE project
Eukaryotic cells make many types of primary and processed RNAs that are found either in specific
subcellular compartments or throughout the cells. A complete catalogue of these RNAs is not yet available
and their characteristic subcellular localizations are also poorly understood. Because RNA represents the
direct output of the genetic information encoded by genomes and a significant proportion of a cell’s
regulatory capabilities are focused on its synthesis, processing, transport, modification and translation,
the generation of such a catalogue is crucial for understanding genome function. We have found that
three-quarters of the human genome is capable of being transcribed, generating thousands of already
known protein coding and non coding RNAs, as well as thousands of previously unknown RNAs. These
observations, taken together, prompt a redefinition of the concept of a gene, which has consequences for
translational biology.
09:30
Xavier Estivill
Centre for Genomic Regulation (CRG). Barcelona, Spain
Human Genome, normal variation and somatic mutations
The human genome sequence shows high variability at the nucleotide and structural levels. This
variabilitity is present in many forms, including nucleotide changes, small deletions and insertions,
rearrangements of genetic material (inversions, deletions and duplications), mobilization of DNA from one
region to another in the genome, and the presence of low copy repeats that contain different copies of
functional elements, including coding and non-coding genes. The ultimate approach to characterize the
variability of the genome is by sequencing the genome of many individuals and defining the genome
references that represent the genomes of all subjects in the human population. This is being achieved by
several projects, which include the 1000 genome project, the UK10K project, and the International Cancer
Genome Consortium project. The analysis of the sequences of these genomes at the structure level should
provide a new step in our understanding of phenotypic variation and disease appearance and progress.
157
10:10
Henk Stunnenberg
Radboud University. Nijmegen, The Netherlands
Epigenetics: a manual for genome function and utilization
Deciphering the human genome sequence has provided critical insight in genome function in relation to
biological processes in health and diseases. Recent technological improvements opened up the analysis
the epigenetic regulation of the information embedded in the genome. Epigenetic regulation
takes place at many levels including of histone modifications, positioning of histone variants, nucleosome
remodeling and DNA accessibility DNA modifications among others and along with transcription factors
and other DNA-binding proteins provide a blueprint. The epigenetic features of each cell type in the body
(>250) are distinct and once established during development and differentiation need to be maintained.
Hence, the study of epigenetic processes go beyond DNA-stored information and provides essential
insight in the manual of the genome, in deciphering derailed processes in disease. I will discuss in detail
the epigenetic mechanisms link to pluripotency.
10:50
11:20
Session 2
11:40
Coffee Break
LARGE SCALE ANALYSIS OF HUMAN GENOME
Chairperson: Carlos Lopez-Otin. Oncology University Institute, University of Oviedo. Spain
Ivo Gut
National Genome Analysis Centre (CNAG). Barcelona, Spain
New sequencing technologies
Nucleic Acid sequencing is one of the most important tools of biological research with very broad
application. Four generations of DNA sequencing technologies can be distinguished by their nature and
the kind of output they provide. Sanger sequencing dominated for 30 years and was the workhorse used
for the Human Genome Project. In 2005 the first 2nd generation sequencer was presented with an output
orders of magnitude higher than Sanger sequencing and dramatically reduced cost per base. Currently, we
are at the dawn of 3rd generation with nanopore systems that are being developed for DNA sequencing.
Meanwhile the field is broadening applications that complement 1st, 2nd and 3rd generation sequencing
systems to get high resolution genetic information and 4th generation sequencing is on the horizon. 2nd
generation nucleic acid sequencers are systematically applied in many large-scale International projects
such as the International Cancer Genome Consortium and the International Human Epigenome Projet
12:20
Alfonso Valencia
Spanish National Cancer Research Centre (CNIO). Madrid, Spain
Data organization, access and mining
Sequencing technology is making of the use of cancer genomic information a pressing clinical need.
Bioinformatics and Computational Biology play a central role in the organization and interpretation of the
genomic information. The Computational workflows required for the analysis of cancer genomes involve
many hurdles related with data structure and integration. Less obvious, but perhaps more important than
the engineering problems, are the scientific challenges related with the interpretation of complex
genomic data. Computational methods are needed for the prediction of the incidence of mutations in the
structure and function of proteins, the comparative analysis of affected pathways, and the extraction of
potentially effective drugs. Our initial experience shows that the many complex challenges in this
emerging area will require a concerted collaborative effort of bioinformaticians, experimental biologist
and cancer clinicians.
13:00
Olivier Delattre
Institut Curie, INSERM-U830. Paris, France
Ewing sarcoma, germline and somatic variations
Ewing sarcoma is the second most frequent primary bone tumor in children. It is mainly observed at the
age of adolescence. The main driver of oncogenesis is gene fusion between EWS family members and ETS
family members, the most frequent being EWS-FLI1. EWS-FLI1 is a transcription factor that can hardly be
directly targeted for therapy. Efforts from many groups worldwide including ours is to identify key EWSFLI1 downstream events that may be actionable. We are also interested by
investigating the peculiar epidemiological profile of Ewing sarcoma which is mainly observed in population
of European descent as compared to population of African or Asian descent. Recently through a genome
wide association analysis we identified 3 loci that are associated with Ewing sarcoma development and
which may genetically interact with EWS.FLI1.
13:40
Mel Greaves
Institute of Cancer Research (ICR). London, UK
Evolution of clonal architectures in acute lymphoblastic leukaemia
Childhood acute lymphoblastic leukaemia (ALL) is commonly initiated in utero (by gene fusion or
hyperdiploidy) and a small fraction of cases (~1%) progresses to clinically overt leukaemia in a relatively
short time frame, usually 3-5 years. Genome sequencing has identified the patterns and number of
mutations involved. Using the comparative genomics of identical twins with ALL, we have tracked the
sequence of genetic events, pre- and post-natally. Single cell analysis by multi-plexed FISH or a microfluidic Q-PCR system (Fluidigm) provides striking evidence of a branching architecture of genetically
distinct subclones. A parallel pattern of genetic diversity is also found in the ALL stem cell population.
14:20
Session 3
16:10
Lunch
LANDSCAPE OF SOMATIC MUTATIONS IN HUMAN CANCER – 1
Chairperson: Elias Campo. Hospital Clínic, University of Barcelona, IDIBAPS. Barcelona, Spain
Serena Nik-Zainal
Wellcome Trust Sanger Institute. Hinxton, Cambridge, UK
Insights from whole-genome sequencing of twenty-one breast cancers
Somatic mutations in a cancer genome report the biological processes of DNA damage and DNA repair
that have been operative over the lifetime of a cancer patient. Harnessing the power of whole-genome
sequencing technology, we set out to extract the mutational signatures characterizing these biological
processes that have been operative in 21 breast cancers.
Multiple distinct single-substitution, double-substitution and deletion signatures were unearthed by these
analyses. Remarkably, these signatures were able to distinguish breast cancers from women with germline
mutations in BRCA1 and BRCA2, indicating how defects in homologous recombination leaves its
mutagenic imprint on cancer genomes.
Furthermore, an intriguing phenomenon of localised hypermutation characterised almost exclusively by
cytosine mutations at TpC dinucleotides, demonstrating marked co-localisation with somatic
rearrangements, was uncovered. These clusters of regional hypermutation were a frequent observation,
occurring in thirteen out of the twenty-one breast cancers studied and have been termed kataegis (greek
for showers/ thunderstorms/towards the earth). The mechanism underlying this mutational signature is
unknown. However, a role for the APOBEC family of cytidine deaminases in kataegis is proposed.
16:50
Carlos López-Otín
Oncology University Institute, University of Oviedo. Spain
The genomic landscape of chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm with two major subtypes characterized by the
mutational status of immunoglobulin genes. However, the molecular alterations leading to the
development and progression of this disease are still poorly understood. The aim of the CLL-ICGC
consortium is to generate a catalogue of genetic alterations relevant to the pathogenesis and clinical
evolution of the disease. By using a combination of whole-genome and exome sequencing of more than
100 CLL cases, we have identified more than 70 new genes that are recurrently mutated in CLL. Functional
analyses of these mutated genes together with clinical studies in a large series of CLL patients have
allowed us to define several genes and molecular pathways that drive the development and progression
of this common form of leukemia.
17:30
Adolfo Ferrando
Institute for Cancer Genetics, Columbia University. New York, USA
Somatic mutations in T-cell neoplasms
Despite recent progress, the prognosis of patients with relapsed and refractory T-cell acute lymphoblastic
leukemia (T-ALL) remains extremely poor. The identification and molecular characterization of T-ALL
oncogenes and tumor suppressors has started to elucidate the genetic and epigenetic mechanisms
mediating T-cell transformation, disease progression and relapse, paving the way for the development of
novel targeted therapies in this disease.
18:10
Reiner Siebert
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein.
Kiel, Germany
Genomic and epigenomic alterations in human lymphoma
Since the description of the Burkitt translocation t(8;14) back in the 1970s the detection of genetic
aberrations in malignant lymphomas has gained constantly diagnostic and clinical importance. Detection
of supposedly primary genetic aberrations is nowadays recommended by the WHO classification for
diagnosis, recurrent secondaty changes can hint to prognosis. Nevertheless, the pattern has become much
more complex through recent genome-wide sequencing and epigenomic profiling analyses pointing to a
much more complicated landscape of (epi)genetic changes in lymphoma. Recent findings and emerging
concepts on lymphoma pathogenesis and evolution and their clinical utility will be discussed.
.
159
th
Friday, November 23
Session 4
08:30
LANDSCAPE OF SOMATIC MUTATIONS IN HUMAN CANCER – 2
Chairperson: Miguel A. Piris. Hospital Marqués de Valdecilla (IFIMAV). Santander, Spain
Ignacio Varela.
Biomedicine and Biotechnology Institute of Cantabria (IBBTEC), University of Cantabria. Santander, Spain
Recurrent somatic mutations in renal cancer
The development of the so-called second-generation sequencing technologies has transformed cancer
research. In the present summary, we emphasize the relevance of the use of these new technologies in
cancer research exemplified by the recent identification of a new cancer gene, PBRM1, found mutated in
more than 30% of clear cell renal carcinomas, the most common subtype of renal cancer. After VHL,
PBRM1 is therefore the second most frequently mutated gene identified to date in this type of tumor and
its study could be of vital importance in the diagnosis, prognosis and treatment of renal cancer.
09:10
Jessica Zucman-Rossi
INSERM-U674. Paris Descartes University. Paris, France
Identification of molecular drivers with new technologies in liver cancer
Hepatocellular carcinoma (HCC) is one leading causes of cancer death in the world and the most frequent
tumor derived from the malignant transformation of hepatocytes. The aim of this study, which is part of
the ICGC (International Cancer Genome Consortium) project, is to identify a catalog of somatic gene
alterations in HCC mostly related to alcohol intake and metabolic syndrome.
Whole-exome sequencing and CGH-SNP were performed on a discovery cohort of 40 and 125 HCC
tumors, respectively. Fourteen master genes, recurrently mutated in exome sequencing, were further
validated by Sanger sequencing in a validation cohort of 300 HCC. Analysis of the results revealed 5
pathways the most frequently altered in HCC: (1) activation of WNT/ß-catenin, (2) cell cycle and p53 (3)
alteration of the chromatin remodeling complexes, (4) activation of the PIK3/MAPK and (5) activation of
the oxidative stress pathways. We also showed that according to different risk factors (infection with
hepatitis viruses, alcohol intake) and according to the underlining chronic liver disease, the pattern of
genes mutated in tumors differed. We will discuss further integration of next generation sequencing data
with other “omics” technologies, clinical and pathological features to better understand mechanisms of
hepatocarcinogenesis in human and how translate these results in clinical practice.
09:50
Joan Seoane
Oncology Institute, University Hospital Vall d'Hebron. Barcelona, Spain
Oncogenomics of brain tumors
Our current model of translational research in the context of brain tumors at Vall d'Hebron Hospital will
be presented. Results obtained from the analysis of the intra-tumoral genomic heterogeneity of
glioblastoma will be shown, taking special interest on its therapeutic implications.
10:30
Session 5
10:50
Coffee Break
CLINICAL PERSPECTIVES IN THE GENOMIC ERA
Chairperson: Hernán Cortés-Funes. Hospital Universitario 12 de Octubre. Madrid, Spain
Xose S. Puente.
Faculty of Medicine, University of Oviedo. Oviedo, Spain
Genomic studies in non-neoplastic diseases
Uncovering the genetic basis of hereditary diseases has been greatly improved by the development of
high throughput sequencing technologies. Due to the high number of variants identified as well as to the
variety of genomic alterations potentially implicated in a disorder, data analysis is challenging and novel
methods are required to extract additional layers of information. Nevertheless, the study of small
pedigrees or very rare diseases underscores the importance of functional validation in any experimental
design.
11:30
Pierre Laurent-Puig
INSERM UMR-S775. Paris Descartes University. Hôpital Européen Georges Pompidou. Paris, France
Diagnostic and prognostic markers in colorectal cancer
To date, no satisfactory predictor of prognosis based on clinical and pathological information is available.
Despite numerous gene expression profile studies on colorectal cancer published in recent years, no
reliable signature has been demonstrated to be useful for clinical practice, especially for prognosis
prediction. Molecular heterogeneity of CCR is one of the major reasons that explain this difficulty. The
molecular classification of colon cancers is currently based on few markers, mainly mismatch repair and
CpG methylation status yielding broad classes, which remain largely heterogeneous, both at the molecular
and clinical levels. No refined molecular classification, as in other main cancers, has been proposed yet.
Establish a robust classification of colorectal based on high-density transcriptome profiles of a large
multicentric cohort is a major issue. From our analysis we revealed six robust molecular subtypes with
distinct clinicopathological, molecular characteristics and deregulated signaling pathways. Moreover, our
classification appeared to be of prognostic interest.
12:10
Elias Campo
Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain
Clinical Impact of Somatic Mutations in Chronic Lymphocytic Leukemia
The recent genomic studies of chronic lymphocytic leukaemia using the next generation of sequencing
technologies have revealed a complex landscape of somatic mutations. The profile of mutated genes
seems different in the two molecular and clinical subtypes of the disease recognized by the IGHV
mutational status. Several genes mutated recurrently such as NOTCH1, SF3B1 and MYD88, occur in subset
of patients with different clinical and biological characteristics. These findings are providing molecular
clues to understand the heterogeneity of the disease and highlight potential targets for new therapies.
12:50
Richard S. Houlston
Institute of Cancer Research. Sutton, Surrey, UK
Genome-wide studies and cancer susceptibility
It has long been speculated that common variation contributes to cancer susceptibility, but robust
evidence for common low-penetrance alleles hasemerged only recently as a result of genome-wide
association studies (GWAS). Such studies have proved a powerful approach for the identification of
common, low-penetrance loci for cancer without prior knowledge of location and function. Over the past
five years GWAS studies have been reported for each of the major cancers in European populations and
several of the less common tumours, including acute lymphocytic leukaemia, myeloma and chronic
lymphocytic leukaemia. Each of these GWAS have reported well-validated new disease loci providing
insight into tumour biology and in many cases disease aetiology.
13:30
Magnus Ingelman-Sundberg
Karolinska Institutet. Stockholm, Sweeden
Pharmacogenomics
The rapid development of techniques in the area of genome analysis has facilitated identification of new
pharmacogenomic biomarkers that can provide predictive tools for improved drug response and reduced
adverse drug reactions. Such biomarkers mainly originate from genes encoding drug-metabolizing
enzymes, drug transporters, drug targets and human leukocyte antigens. Some of these are now
integrated by the USA Food and Drug Administration and the European Medicines Agency into drug label
inserts. In this lecture, the utility and mechanistic background of pharmacogenomic biomarkers in the
area of cancer will be discussed.
14:10
Farewel & Closure / Despedida y Clausura
14:20
Almuerzo / Lunch
Mariano Barbacid, Elias Campo, Carlos López-Otín, Jose A. Gutierrez-Fuentes, M. A. Piris y Hernán Cortes Funes
INFORMATION
Conferences: 30-minute talk; 10-minute discussion after each talk / English <> Spanish simultaneous translation
Seminarios: Intended for the discussion and orientation of practical aspects related with the prevention, diagnosis and treatment (limited
groups. Only Spanish)
Mariano Barbacid, Carlos López-Otín, Elias Campo y José A Gutiérrez-Fuentes
EUROFORUM Campus INFANTES, San Lorenzo de El Escorial, Madrid
INFORMACIÓN EN: (+34) 91 781 50 70 ● [email protected]
161
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