Future perspectives in melanoma research: meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014.

The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma.

Prescription médicamenteuse inappropriée: les nouveaux critères STOPP/START [Prescribing inappropriate medication: the new STOPP/START criteria].

Prescribing inappropriate medication (PIM) is a common public health problem. Mainly due to associated adverse drugs events (ADE), it results in major morbidity and mortality, as well as increased healthcare utilization. For a long time, the systematic review of medications prescribed appeared as a solution for limiting PIM and the ADE associated with such prescriptions. With this aim and since 2008, the list of STOPP-START criteria has appeared as attractive in its design, as well as logical and easy to use. The initial version has just been updated and improved. After having detailed all improvements provided to the 2008 version, we present the result of its adaptation into French language by a group of French-speaking expert from Belgium, Canada, France, and Switzerland.

Les critères STOPP/START.v2 : adaptation en langue française. [STOPP/START.v2 criteria: Adaptation into French language]

Objectif STOPP/START est un outil de détection de la prescription médicamenteuse potentiellement inappropriée chez la personne de 65 ans ou plus. La version initiale de 2008 vient d'être mise à jour et améliorée par ses auteurs. Nous en présentons l'adaptation et la validation en langue française. Méthodes L'adaptation en français de l'outil STOPP/START.v2 a été réalisée par deux experts, confirmée par la méthode de traduction-inverse, et finalisée d'après les commentaires de neufs évaluateurs francophones, gériatres, pharmaciens cliniciens, et médecin généraliste de quatre pays (France, Belgique, Suisse, Canada). La validation a été complétée par une analyse de concordance inter-juge (CCI) des critères STOPP/START.v2 appliqués à dix vignettes cliniques standardisées. Résultats Les 115 critères de STOPP/START.v2 en français sont, par rapport à la version originale anglaise, identiques par leur classification mais adaptés en termes de présentation (critères START.v2 commençant par la condition clinique, et accompagnés par une justification du caractère inapproprié de l'omission) voire de formulation de certains critères. Cette adaptation en français est validée par (i) la traduction-inverse montrant le respect du sens clinique de la version originale, (ii) l'identification semblable des critères lorsque appliqués à dix vignettes cliniques par les neuf évaluateurs, et (iii) le haut niveau de concordance de ces neuf évaluations tant pour STOPP.v2 (CCI 0,849) que pour START.v2 (CCI 0,921). Conclusion L'adaptation en langue française des critères STOPP/START.v2 fournit aux cliniciens un outil de détection de la prescription médicamenteuse potentiellement inappropriée chez les personnes de 65 ans et plus qui est logique, fiable et facile à utiliser. Objective STOPP/START is a screening tool to detect potentially inappropriate prescribing in persons aged 65 or older. Its Irish authors recently updated and improved the initially published version of 2008. We present the adaptation and validation into French language of this updated tool. Methods STOPP/START.v2 was adapted into French by two experts, then confirmed by a translation-back translation method and finalised according to the comments of nine French-speaking assessors - geriatricians, pharmacologists and a general physician - from four countries (France, Belgium, Switzerland, and Canada). The validation was completed by an inter-rater reliability (IRR) analysis of the STOPP/START.v2 criteria applied to 10 standardized clinical vignettes. Results In comparison to the original English version, the 115 STOPP/START.v2 criteria in French language classify in identical manner, but the presentation has been adjusted (START.v2 first specifies the clinical condition followed by an explanation of the inappropriateness of the prescription or omission). This adaptation into French language was validated by means of (i) the translation/back-translation, which showed that the French version complied with the clinical meaning of the original criteria; (ii) the similar screening results when applied by the nine specialists to the 10 cases; and (iii) the high level of inter-rater reliability of these 9 evaluations, for both STOPP (IRR 0.849) and START.v2 (IRR 0.921). Conclusion The adaptation into French of the STOPP/START.v2 criteria provides clinicians with a screening tool to detect potentially inappropriate prescribing in patients aged 65 and older that is more logical, more reliable and easier to use.

Pitkän käyttöiän web-sovelluksen toteuttaminen

Tässä työssä selvitettiin hyviä tapoja ja vakiintuneita käytäntöjä pitkän käyttöiän web-sovelluksen tekemiseksi. Saatiin selville, että sovelluksen elinkaaren aikana suurin osa kustannuksista tulee ylläpidosta. Tavoitteena oli tehdä pitkään käytettävä sovellus, joten ylläpidon kustannusten osuudesta tuli saada mandollisimman pieni. Ohjelmistotuotantoprosessissa mandollisimman aikaisessa vaiheessa havaitut virheet vähentävät korjauskustannuksia oleellisesti verrattuna siihen, että virheet havaittaisiin valmiissa tuotteessa. Siksi tässä työssä tehdyssä web-sovelluksessa panostettiin prosessin alkuvaiheisiin, määrittelyyn ja suunnitteluun. Web-sovelluksen ylläpidettävyyteen ja selkeyteen vaikuttavat oleellisesti hyvät ohjelmistokehitystavat. Käyttämällä valmista sovelluskehystä ja lisäämällä toiminnallisuuksia valmiiden ohjelmistokomponenttien avulla saadaan aikaiseksi hyvien tapojen mukaisesti tehty sovellus. Tässä työssä toteutettu web-sovellus laadittiin käyttämällä sovelluskehystä ja komponenttiarkkitehtuuria. Toteutuksesta saatiin selkeä. Sovellus jaettiin loogisiin kokonaisuuksiin, jotka käsittelevät näkymiä, tietokantaa ja tietojen yhdistämistä näiden välillä. Jokainen kokonaisuus on itsenäisesti toimiva, mikä auttaa sovelluksen ylläpitämisessä ja testaamisessa.

World Polarization in carbon emissions, potential conflict and groups: an updated revision

Typically, conflicts in world environmental negotiations are related, amongst other aspects, to the level of polarization of the countries in groups with conflicting interests. Given the predictable relationship between polarization and conflict, it would seem logical to evaluate the degree to which the distribution of countries – for example, in terms of their CO2 emissions per capita – would be structured through groups which in themselves are antagonistic, as well as their evolution over time. This paper takes the concept of polarization to explore this distribution for the period 1992-2010, looking at different analytic approaches related to the concept. Specifically, it makes a comparative evaluation of the results associated with endogenous multi-polarization measures (i.e. EGR and DER indices), exogenous measures (i.e. Z-K or multidimensional index) and strict bipolarization measures (i.e. Wolfson’s measure). Indeed, the interest lies not only in evaluating the global situation of polarization by comparing the different approaches and their temporal patterns, but also in examining the explanatory capacity of the different proxy groups used as a possible reference for designing global environmental policy from a group premise. JEL codes: D39; Q43; Q56. Key words: polarization; carbon emissions; conflict;

Simple Heuristics in a Social Game

Simple Heuristics in a Social World invites readers to discover the simple heuristics that people use to navigate the complexities and surprises of environments populated with others. The social world is a terrain where humans and other animals compete with conspecifics for myriad resources, including food, mates, and status, and where rivals grant the decision maker little time for deep thought, protracted information search, or complex calculations. Yet, the social world also encompasses domains where social animals such as humans can learn from one another and can forge alliances with one another to boost their chances of success. According to the book's thesis, the undeniable complexity of the social world does not dictate cognitive complexity as many scholars of rationality argue. Rather, it entails circumstances that render optimization impossible or computationally arduous: intractability, the existence of incommensurable considerations, and competing goals. With optimization beyond reach, less can be more. That is, heuristics--simple strategies for making decisions when time is pressing and careful deliberation an unaffordable luxury--become indispensible mental tools. As accurate as or even more accurate than complex methods when used in the appropriate social environments, these heuristics are good descriptive models of how people make many decisions and inferences, but their impressive performance also poses a normative challenge for optimization models. In short, the Homo socialis may prove to be a Homo heuristicus whose intelligence reflects ecological rather than logical rationality.

Bidding support for computational resources

Peer-reviewed

Many valued algebraic structures as measures of comparison

This thesis studies the properties and usability of operators called t-norms, t-conorms, uninorms, as well as many valued implications and equivalences. Into these operators, weights and a generalized mean are embedded for aggregation, and they are used for comparison tasks and for this reason they are referred to as comparison measures. The thesis illustrates how these operators can be weighted with a differential evolution and aggregated with a generalized mean, and the kinds of measures of comparison that can be achieved from this procedure. New operators suitable for comparison measures are suggested. These operators are combination measures based on the use of t-norms and t-conorms, the generalized 3_-uninorm and pseudo equivalence measures based on S-type implications. The empirical part of this thesis demonstrates how these new comparison measures work in the field of classification, for example, in the classification of medical data. The second application area is from the field of sports medicine and it represents an expert system for defining an athlete's aerobic and anaerobic thresholds. The core of this thesis offers definitions for comparison measures and illustrates that there is no actual difference in the results achieved in comparison tasks, by the use of comparison measures based on distance, versus comparison measures based on many valued logical structures. The approach has been highly practical in this thesis and all usage of the measures has been validated mainly by practical testing. In general, many different types of operators suitable for comparison tasks have been presented in fuzzy logic literature and there has been little or no experimental work with these operators.

Solubilidade do SrO em NaCl-Kcl fundido a 727ºC

The solubility product value of SrO has been found to be equal to 10-4,2 (molality scale) in molten equimolar mixture of NaCl and KCl at 727ºC, using a potentiometric method involving a calcia stabilized zirconia membrane electrode. This value, which is in a logical agreement with other alkaline-earth oxide determined solubilities, is compared to those of 10-5,8, 10-3,0 and 10-3,08 (molality scale) found in the litterature 33, 22 and 5 years ago, respectively. Such discrepencies have called the attention of the authors, their possible reasons (methodology, titrating agent) are analyzed and a theoretical discussion, for considering the authors' value as more reliable, is given in this paper.

Discusión sobre la influencia de la corriente criminológica positivista en el discurso penal argentino.

En 10s últimos siglos diferentes corrientes de pensamiento europeas han reflexionado acerca de las características del Derecho y de la practica jurídica. Varias tendencias se han ido disputando el interds de 10s juristas especialmente en el campo delictual y en el contexto de la consolidacion de la institución carcelaria como ámbito central de ejecución de la pena privativa de libertad. En materia de Derecho Penal las dos orientaciones mas importantes de 10s siglos XVLII y XIX fueron el Positivismo y el Iluminismo (I), un debate que ilegó mas tardíamente y con menor fuerza a Argentina pero que fue una manifestación de la incorporación de 10s juristas al for0 internacional. Esa incorporación coincidia con Ia consolidacion de la criminologia positivista en Europa, fundada en el análisis de la personalidad del delincuente, en la utilización de métodos de las ciencias naturales y en paradigmas epistemológicos de tip etiolbgico: 10s representantes de esta corriente explicaban la criminalidad examinand0 las causas y 10s factores desde un punto de vista bislógico (2).

Mourning Becomes Electra by Eugene O’Neill: Aeschylus and Plato’s Cave to Create a Dark Drama

The fundamental debt of E. O’Neill’s Mourning Becomes Electra to Aeschylus, and to a lesser degree to Sophocles and Euripides, has been always recognised but, according to the author’s hypothesis, O’Neill might have taken advantage of the Platonic image of the cave in order to magnify his both Greek and American drama. It is certainly a risky hypothesis that stricto sensu cannot be proved, but it is also reader’s right to evaluate the plausibility and the possible dramatic benefit derived from such a reading. Besides indicating to what degree some of the essential themes of Platonic philosophy concerning darkness, light or the flight from the prison of the material world are not extraneous to O’Neill’s work, the author proves he was aware of the Platonic image of the cave thanks to its capital importance in the work of some of his intellectual mentors such as F. Nietzsche or Oscar Wilde. Nevertheless, the most significant aim of the author’s article is to emphasize both the dramatic benefits and the logical reflections derived, as said before, from reading little by little O’Neill’s drama bearing in mind the above mentioned Platonic parameter.

Câmaras climáticas para o envelhecimento acelerado: ação de microambientes sobre bens culturais

Environmental chambers were designed for the accelerated ageing of materials used in artistic artifacts to study the synergistic action of temperature, humidity, UV and visible radiation and gaseous pollutants. Two inox-steel/PTFE compartments are kept under controlled temperature and relative humidity, whose values are transmitted to a PC, which stores, plots in real time and continuously feedback heating and humidifying devices through logical signals. A borosilicate, or quartz, window allows the irradiation inside the chamber from an external source. A flow of purified air purges the chamber and conveys selected pollutants from an external source. Each independent compartment works under either stationary or cyclic conditions.

Constantes de acidez de ácidos dipróticos a partir de titulações potenciométricas: ilustração dos princípios do cálculo através da construção de um algoritmo muito simples

This work describes the creation of an very simple calculation algorithm, based in basic chemical and mathematic principles, for the calculation of weak diprotic acid dissociation constants as, for example, amino acids, from potentiometric titrations. For an easier understanding of the algorithm the logical reasoning of this calculus is schematized in a diagram of blocks. In the second part of the work the algorithm is applied to an Excel calculation sheet to determine the dissociation constants of Nicotinic Acid and Glycine, from the respective potentiometric titration curves. The values obtained using this algorithm are compared with those estimated by Hyperquad2008 (program generally used for this type of calculus) and also with the values of a stability constants database.

Suunnitelma WWW-palvelun monikanavaistamiseksi

Tämän diplomityön tavoitteena on kuvata suunnitelma, jossa alun perin WWW-ympäristöön kehitettyä palvelua muokataan siten, että palvelu skaalautuu mahdollisimman hyvin tulevaisuuden laajennuksiin. Selainpohjaisten palveluiden lisäksi esimerkiksi mobiili-palvelut ja erilaiset työpöytäsovellusintegraatiot ovat kasvattaneet suosiotaan. Samoin eri palveluiden välisestä yhteistoiminnasta on kasvanut merkittävä osa Internet-palveluiden loppukäyttäjilleen tarjoamaa palvelukokonaisuutta. Esimerkkejä WWW-palveluiden integroinneista päätelaitteille ovat hakukoneiden ja pikaviestimien mobiili-versiot, ja palveluiden yhteistoiminnasta erilaisten uutispalveluiden ja sosiaalisten palveluiden, kuten Facebook, väliset yhteisölinkitykset. Tässä diplomityössä selvitetään aluksi Internet-pohjaisten palveluiden kehitystä sekä tutustutaan tarkemmin palveluiden monikanavaisuuteen. Tämän jälkeen käydään läpi loppukäyttäjien saatavilla olevia päätelaitteita verkkoyhteyksineen ja WWW-palveluiden suunnittelumalleja. Suunnittelun lähtökohtana oli se, että erilaisten päätelaitteiden, päätelaitteiden ohjelmistojen ja käytössä olevien verkkoyhteyksien muodostamien palvelualustojen liittäminen palveluun olisi mahdollisimman yksinkertaista. Ja tukea uusien palvelualustojen käyttäjien ja sisällön sovittamista olemassa olevaan palveluun. Työn lopputuloksena on suunnitelma, joka pohjautuu välikerroksen rakentamiseen uusien palvelualustojen ja vanhan palvelun väliin. Palveluun tarjotaan välikerroksen kautta personoitu rajapinta luotetuille asiakkaille sekä kaikille avoin julkinen rajapinta. Välikerros suunniteltiin yksinkertaisella REST-arkkitehtuurityylillä, mikä mahdollistaa palvelun tarjonnan turvallisesti ja tehokkaasti. Tähän välikerrokseen lisätään käyttäjän- ja sisällönhallinnan komponentteja pitämään huolen palvelun eheydestä. Tämä diplomityö osoittaa, että oikealla arkkitehtuurilla suunniteltu monikerroksinen väliohjelmisto tarjoaa tehokkaan tavan integroida ja hallinnoida uusia alustoja.

THE FORMAL AND THE FORMALIZED: THE CASES OF SYLLOGISTIC AND SUPPOSITION THEORY

As a discipline, logic is arguably constituted of two main sub-projects: formal theories of argument validity on the basis of a small number of patterns, and theories of how to reduce the multiplicity of arguments in non-logical, informal contexts to the small number of patterns whose validity is systematically studied (i.e. theories of formalization). Regrettably, we now tend to view logic 'proper' exclusively as what falls under the first sub-project, to the neglect of the second, equally important sub-project. In this paper, I discuss two historical theories of argument formalization: Aristotle's syllogistic theory as presented in the "Prior Analytics", and medieval theories of supposition. They both illustrate this two-fold nature of logic, containing in particular illuminating reflections on how to formalize arguments (i.e. the second sub-project). In both cases, the formal methods employed differ from the usual modern technique of translating an argument in ordinary language into a specially designed symbolism, a formal language. The upshot is thus a plea for a broader conceptualization of what it means to formalize.