Epigenetic treatment of solid tumours. A review of clinical trials

Epigenetic treatment has been approved by regulatory agencies for haematological malignancies. The success observe in cutaneous lymphomas represents a proof of principle that similar results may be obtained in solid tumours. Several agents that interfere with DNA methylation-demethylation and histones acetylation/deacetylation have been studied, and some (such as azacytidine, decitabine, valproic acid and vorinostat) are already in clinical use. The aim of this review is to provide a brief overview of the molecular events underlying the antitumour effects of epigenetic treatments and to summarise data available on clinical trials that tested the use of epigenetic agents against solid tumours. We not only list results but also try to indicate how the proper evaluation of this treatment might result in a better selection of effective agents and in a more rapid development. We divided compounds in demethylating agents and HDAC inhibitors. For each class, we report the antitumour activity and the toxic side effects. When available, we describe plasma pharmacokinetics and pharmacodynamic evaluation in tumours and in surrogate tissues (generally white blood cells). Epigenetic treatment is a reality in haematological malignancies and deserves adequate attention in solid tumours. A careful consideration of available clinical data however is required for faster drug development and possibly to re-evaluate some molecules that were perhaps discarded too early

Modelli e metodi di ottimizzazione in ambito Home Care: approcci robusti

L'Home Care è una metodologia di assistenza sanitaria sempre più diffusa, grazie ai riscontri positivi sulla qualità di vita dei pazienti, che possono avvalersi delle cure presso i loro domicili, e ad un non trascurabile vantaggio economico per l'ente che rilascia il servizio. Per questo, numerosi autori hanno proposto differenti modelli e metodi deterministici di supporto alle decisioni per l'assegnazione dei pazienti agli operatori e la generazione di tour ammissibili per questi ultimi. In letteratura rimangono, tuttavia, poco trattati gli approcci robusti e questi si limitano a considerare la variazione di disponibilità degli operatori e i tempi di servizio stocastici. In questo elaborato viene proposto un modello robusto, a partire da un modello deterministico proposto in letteratura, che considera scenari caratterizzati da richieste sia certe, che incerte. Notevole importanza viene conferita ai risultati computazionali, ottenuti dalla sperimentazione di istanze reali opportunamente modificate per considerare elementi di incertezza, al variare di alcuni specifici parametri. Dai test eseguiti, risulta che il modello ILP proposto sia di buona qualità per le istanze di medio-piccole dimensioni e riesca a garantire un buon bilanciamento di carico lavorativo tra gli operatori

Peptide and drug interactions in murine models : in vitro and in vivo studies with microphysiometry, confocal microscopy and functional magnetic resonance imaging

The present thesis describes in three parts how living cells can be investigated on different biological levels, and how these techniques can be used to non-invasively evaluate the effect of drugs in the context of biomedical and pharmaceutical research. In the first part, Pgp activation is studied in living cells studied in culture. Here, microphysiometry, monolayer techniques and computer modeling were applied to investigate the interaction of drugs with human P-glycoprotein (Pgp). Pgp is a transmembrane ABCtransporter that protects cells from a wide variety of toxic substances. Pgp is helpful under most biological conditions since it provides natural protection from toxins, but its activity can lead to resistance development in chemotherapy e.g. of cancers and microbes. In particular, the reported techniques provided a novel method to study Pgp-substrate interactions in realtime and in living murine cellular systems in which human Pgp have been expressed. Investigation of Pgp-substrate interactions is then extended to the structure-activity relationships (SAR) of potential Pgp substrates, on the basis of a recognition mechanism based on intramolecular hydrogen bond acceptor patterns. In the second part, living cultured murine cells were studied under the influence of cell penetrating peptides (CPPs). CPPs are a class of compounds that traverse biological membranes very efficiently, although the precise uptake mechanism is not yet known. Elucidation of the exact uptake mechanism is, however, of great interest, given the potential of this class of compounds for pharmacological and biotechnological purposes. A CPP derived from the HIV-1 peptide TAT was studied using fluorescence confocal microscopy and microphysiometry as principal techniques. In the third part of the thesis, the biological observation level was switched from living cells in culture to the entire organism using magnetic resonance imaging as a non-destructive method to observe biological effects of drugs. In pharmaceutical research the development of a commercial compound requires similar observation levels during the long evaluation process starting from high throughput screening of potential bioactive molecules and ending with the launch of one selected therapeutically successful product. The intermediate steps include basic in vitro studies, in vivo experimentation with cell culture, pre-clinical assays with intact animal models and phase I-III clinical trials with humans. For ethical and practical reasons, major attempts are made to replace invasive animal models by non-invasive techniques that can be applied in the same way to the clinical research providing thus a smooth transition between pre-clinical and clinical phases. This last part of the thesis adapts and optimizes such a recent imaging method to detect brain activation non-invasively in mice and to allocate the activated brain areas in mice without the need for surgery. In particular, the study focused on the activation of metabotrobic GABA(B) receptors in the mouse brain, upon stimulation with baclofen. The technical goal of this project was to adapt functional magnetic resonance imaging (fMRI) protocol at high field (7T) to the small size of the murine brain. The biological goal was to characterize regions in the brain, that show an enhanced activity under the influcence of baclofen - a know stimulator of GABAB receptors

Educación, bien común y mercado

Valentín LetelierEl Estado y la educación nacional  

Three resilient megastructures by Pier Luigi Nervi

Resilience, as the ability of a structure to withstand threats and continue to function, it is normally related to durability and performance to accepted standards over time. The resilience of a structure can be threatened by poor design, changes in the public's perception of style, the potential for a change-in-use and structural attack; catastrophic events such as fire, explosion or impact are usually considered the main threats for Resilience. In the contemporary built environment Resilience is considered increasingly important; it has, in fact, become one of the major design issues, especially for large, iconic or public and prominent structures: this has not always been the case. Following the Second World War, building designers faced the necessity to conceive projects within severe financial constraints, hence the proliferation of a low quality and limited life-span structures; buildings which were designed to be replaceable, cheap and perhaps anonymous. This was thought to be an effec-tive answer to quickly accommodate the large number of people moving towards the urban environment partly destroyed by the WWII. These very buildings now constitute the backbone of our urban scenery and although some still function adequately, many are perfect examples of structures which exhibit a lack of re-silience. Fortunately, there were a few designers who refused this post-war tendency and attempted to design lasting structures of quality: most of them were engineers. This is not a coincidence, engineers had less to do with the issue of providing residential accommodations and more with the erection of large structures which necessitated a higher quality control on materials and technologies: Pier Luigi Nervi was one of them. This work considers three large structures designed and built fifty years ago,in 1961, by the Italian engineer. The structures are the Bus Station at the George Washington Bridge in New York (USA); The Burgo Paper Mill in Mantua (Italy); and the Palace of Labour in Turin (Italy). All of these buildings are hybrid structures (concrete and steel), an unusual choice for Nervi that perhaps reects the design climate at the time; These buildings reacted quite differently to the events that have occurred over the past half century. One of the key factors to achieve resilience it is considered to be the quality of the buildings, which includes their ability to perform maintenance. The lack of which for whatever reason, this paper aims to demonstrate, will inevitably result in a weak performance in terms of resilience on the long run

La fundamentalidad del comportamiento y la reforma educacional en curso discurso de apertura, escuela de temporada Universidad de Chile, enero de 1998

La Reforma Educacional que se está llevando a efecto en nuestro país se define como tal sólo a partir del discurso presidencial del 01 de mayo de 1996 aunque su gestación se remonta a 1990, año de la asunción del primer gobierno democrático, al término del largo período autoritario. Por lo tanto, hoy se está iniciando prácticamente el octavo año de un intenso y decidido trabajo dedicado a lo que se ha dado en denominar globalmente "la modernización del sistema educacional", cuyas razones originarias, fundantes y políticamente consensuales, se ubican en el documento "Los Desafíos de la Educación Chilena frente al Siglo XXI" elaborado por el Comité Técnico Asesor del Diálogo Nacional sobre la Modernización de la Educación, profusamente divulgado en el contexto nacional y en países latinoamericanos que se inspiran en sus directrices, con el propósito también de nutrir la propia reflexión e implementar las transformaciones que el término de milenio exige, prácticamente, a todos los sistemas escolares.