De Hiroshima a Txernòbil: efectes carcinogènics i impacte social de la radiació ionitzant

Hom descriu l'efecte carcinogènic de la radiació, en especial la deguda a la contaminació per accidents de centrals nuclears. El possible mecanisme d'acció, així com la comparació dels efectes de la radiació amb els produïts pels carcinògens químics, hi són tractats concisament. Hom considera les conseqüències del desastre de Txernòbil amb l'escampadissa de radioactivitat per Europa en els aspectes sanitari, psicològic, social i polític, i hi delinea unes estratègies de protecció civil per al cas d'una possible contaminació radioactiva als Països Catalans. L'extraordinària concentració de centrals nuclears a Catalunya es indicada com a una raó fonamental per a adoptar mesures de detecció de la radioactivitat, evacuació de zones afectades, tractament terapèutic i descontaminació. Hi és examinat el problema de la contaminació per radó i la seva possible incidència a Catalunya. El debat sobre els riscs immediats i imponderables de l'energia nuclear (explosions, contaminació radioactiva) i els de l'energia convencional termoelèctrica (pol•lució atmosfèrica, efecte d'hivernacle), és revisat succintament. Com a projecció pragmàtica i d'acord amb les declaracions acordades en algunes de les Trobades anteriors, hom fa unes propostes de mesures concretes i adequades, des de la formació d'equips tècnics de salvament fins a la informació i educació de professionals i públic per a afrontar emergències de contaminació nuclear. Com a conclusió, hom considera 1'equació: home + màquina = progrés experimentant una davallada en demostrar la fal•libilitat de la tecnologia. Essent "l'àtom el mateix per a la pau com per a la guerra", hom suggereix la proposta utòpica de "desmantellar l'àtom" com a sortida extrema del malson nuclear.This paper deals with the carcinogenic effect of ionizing radiation, especially from fallout due to accidents in nuclear plants and its social impact. The possible mechanism of action of radiation as well as the comparison of its effect with those of chemical carcinogens, is briefly described. The results of the Chernobyl disaster with the concomitant radioactive fallout throughout Europe, is reviewed from the stand point of its effects on health and public reactions at all levels. Strategies of civil defense in case of nuclear accidents in Catalonia are briefly outlined. The extraordinary concentration of nuclear plants in Catalonia, makes mandatory the adoption of preventive measures. The problem of natural contamination by radon in homes, is briefly examined. The debate over the riscs, both immediate and long-range, of nuclear energy (explosions, radioactive contamination) is concisely discussed. Following previous declarations at meetings of scientists at the "Universitat Catalana d'Estiu" at Prada, proposals for concrete measures, are presented. It is felt that the equation: man + machine = progress, has suffered a setback with the demonstration of the fallibility of man and technology. The apparently utopian proposal of "dismantling the atom", is suggested as the only way out from the nuclear nightmare

Contaminació carcinogènica i potencial de prevenció

Hom discuteix el problema de la contaminació carcinogènica des del punt de vista del seu context universal i del seu remot origen. Els presents factors de contaminació són atribuïts a l'augment de població urbana, a la sempre creixent industrialització i a la pol•lució radioactiva. Hom dóna una importància especial als efectes causats per substàncies químiques, pel fet d'haver estat determinat que la majoria de casos de càncer humà serien el resultat de la interacció de diversos carcinògens d'origen endogen o exogen. Altres factors, físics (radiacions) i biològics (genètics i viràsics) són en l'actualitat de menor incidència en comparació amb la carcinogènesi química. Hom delinea una distinció entre els conceptes de «carcinogen» i «factor de risc carcinogènic», tot indicant el lligam incontrovertible o putatiu, respectivament, entre causa i efecte. Entre els primers, el tabaquisme sobresurt com a causa principal de càncer en països industrialitzats. El debat i els punts de vista oposats sobre la diversa etiologia del càncer es revisada succintament. Dins el context de l'emergència de carcinògens durant el període d'evolució, hom proposa una hipòtesi sobre el possible origen de la cel•lula cancerosa per l'efecte de carcinògens naturals. Una anàlisi del procés evolutiu del regne vegetal sembla donar suport a la idea que s'ha produït des del Mesozoic una creixent descontaminació del planeta pel que fa a carcinògens naturals. Aquesta tendència sembla revertida per la present invasió tecnològica, amb la pol•lució conseqüent. Hom suggereix algunes normes per a una possible prevenció de la carcinogènesi ambiental, que podria traduir-se en una disminució significativa de la incidència de càncer en el futur.The problem of carcinogenic contamination is discussed from the point of view of its global, universal context and its remote origin. The current factors of ontamination are attributed to the increase of urban population, the evergrowing industrialitzation and the radioactive materials. An emphasis is given to the effects caused by chemical substances as it has been determined that the majority of cases of human cancer can be a result of the interaction of many carcinogens of exogenous or endogenous origin. Other types of factors, physical (radiation) and biological (genetic and viral) are, at the present, of lesser significance when compared with chemical carcinogenesis. A distinction is made between «carcinogen» and «factor of carcinogenic risk» to indicate the absolute or putative connection between cause and effect. Among the first, tobacco stands out as the main cause of cancer among industrialized countries. The debate and the opposed views on the cancer etiology is briefly reviewed. Within the context of the emergence of carcinogens, during the whole evolutionary process, a hypothesis is advanced on the possible origin of the malignant cell by environmental contamination. An analysis of the process of evolution in the plant kingdom lends support to the idea that an increasing de-contamination of the planet regarding carcinogenic substances has taken place since the Mesozoic era. This trend seems to be reversed by the present technological invasion. Some suggestions are put forward about the potential for prevention of environmental carcinogenesis which could lead to a significant reduction in the incidence of cancer in the future

Characterization of colon cancer stem cells and their response to treatment with extracts of medical plants

Il cancro del colon-retto è una delle neoplasie più frequenti, ad alto tasso di mortalità, causato dall’interazione di fattori genetici e ambientali. Parallelamente al modello stocastico, secondo il quale tutte le cellule tumorali (CT) hanno una stessa probabilità di rigenerare un tumore, sta prendendo piede il modello che vede solamente in un piccolissimo sottogruppo di cellule staminali tumorali (CST) la capacità di dar luogo e sostenere la crescita tumorale. Dalla letteratura si evince come le CST mostrino deregolazioni a carico di geni implicati in: chemio-resistenza, transizione epitelio-mesenchimale (EMT), auto-rinnovamento incontrollato, processi peculiari delle CST, che favoriscono l’insorgenza di un fenotipo tumorale. Lo scopo del progetto di Dottorato è stato quello di isolare e caratterizzare le CST sia da linee cellulari tumorali che da biopsie di tumore al colon-retto, per identificare marcatori tumorali utili a delineare le fasi di progressione del tumore e di individuare potenziali bersagli terapeutici. Inoltre, ho sottoposto le CT e le CST di una linea di adenocarcinoma del colon-retto (HCA7), a trattamento con l’estratto naturale di T. cordifolia, pianta utilizzata della medicina Ayurvedica, ed uno dei suoi principi attivi, la berberina, allo scopo di verificarne l'efficacia antitumorale. Ho osservato importanti deregolazioni nelle popolazioni cellulari trattate, a carico di diversi geni coinvolti principalmente nella EMT, nella regolazione del ciclo cellulare e della apoptosi e nel favorire un fenotipo chemio-resistente. I livelli di espressione di questi geni sono risultati essere significativamente sotto-espressi, sia nelle CT trattate che nelle CST trattate. I risultati che ho ottenuto depongono a favore di un potenziale ruolo attivo della sostanza naturale sottoposta ad indagine, nel contrastare molti di quei processi fondamentali per lo sviluppo di un fenotipo tumorale. Inoltre, i miei dati avvallano anche l’ipotesi che vede le CST come potenziali bersagli terapeutici, per ottenere un effetto mirato su questa popolazione cellulare tumorale.Colorectal cancer is one of the most frequent cancer, with a high mortality rate, caused by the interaction of genetic and environmental factors. Parallel to the stochastic model, according to which all tumor cells (CT) have the same probability of regenerating a tumor, there is a new model that look in a very small subset of cancer stem cells (CST) the responsible of tumor growth. In the literature, CSTs shows important deregulations on genes implicated in: chemo-resistance, epithelial-mesenchymal transition (EMT), uncontrolled self-renewal, peculiar processes of this small subpopulation, which favor the onset of a tumor phenotype . The aim of my PhD project was to isolate and characterize CSTs both from tumor cell lines and from colorectal cancer biopsies, in order to identify tumor markers useful for delineating the phases of tumor progression and identifying potential therapeutic targets. In addition, I treated the CT and CST of a line of colorectal adenocarcinoma (HCA7) with the natural extract of T. cordifolia, a plant used in Ayurvedic medicine, and one of its active ingredients, berberine, in order to verify its antitumor efficacy. I observed important deregulations in treated cell populations, dependent on several genes involved mainly in EMT, in cell cycle regulation and apoptosis, but also in promoting a chemo-resistant phenotype. The expression levels of these genes were found to be significantly under-expressed, both in the treated CTs and in the treated CSTs. The results I have obtained are in favor of a potential active role of the investigated natural substance, in countering many of those fundamental processes for the development of a tumor phenotype. Furthermore, my data also support the hypothesis that CSTs are potential therapeutic targets for the purpose of achieving a targeted effect on this cell tumor population

Methylation status of Vitamin D receptor gene promoter in benign and malignant adrenal tumors

We previously showed a decreased expression of vitamin D receptor (VDR) mRNA/protein in a small group of adrenocortical carcinoma (ACC) tissues, suggesting the loss of a protective role of VDR against malignant cell growth in this cancer type. Downregulation of VDR gene expression may result from epigenetics events, that is, methylation of cytosine nucleotide of CpG islands in VDR gene promoter. We analyzed methylation of CpG sites in the VDR gene promoter in normal adrenals and adrenocortical tumor samples. Methylation of CpG-rich 5' regions was assessed by bisulfite sequencing PCR using bisulfite-treated DNA from archival microdissected paraffin-embedded adrenocortical tissues. Three normal adrenals and 23 various adrenocortical tumor samples (15 adenomas and 8 carcinomas) were studied. Methylation in the promoter region of VDR gene was found in 3/8 ACCs, while no VDR gene methylation was observed in normal adrenals and adrenocortical adenomas. VDR mRNA and protein levels were lower in ACCs than in benign tumors, and VDR immunostaining was weak or negative in ACCs, including all 3 methylated tissue samples. The association between VDR gene promoter methylation and reduced VDR gene expression is not a rare event in ACC, suggesting that VDR epigenetic inactivation may have a role in adrenocortical carcinogenesi

SVILUPPO DI INIBITORI DI PDK1 A STRUTTURA 2-OXOINDOLONICA

Il processo di carcinogenesi è il risultato di un alterato bilancio tra i fenomeni fisiologici di divisione e crescita cellulare e il normale processo di morte programmata (apoptosi). Nel contesto di questo delicato bilancio, proteine e vie di trasduzione del segnale che regolano la crescita, il differenziamento, e lo sviluppo cellulare spesso subiscono alterazioni genetiche che inducono modifiche oncogeniche. Il pathway di PDK1/Akt è una delle vie di segnalazione più importanti nei meccanismi di crescita e sopravvivenza cellulare