Predictive carboplatin treatment response models for epithelial ovarian cancer : comparison of 2D, 3D and in-vivo models

L’adénocarcinome épithélial de l’ovaire (CEO) est le cancer gynécologique le plus mortel. La recherche de nouvelles thérapies repose principalement sur des modèles précliniques 2D et in vivo avec des lignées cellulaires (LC) pour générer les évidences nécessaires à l’initiation d’essais cliniques. Ce processus requiert des fonds substantiels en recherche/santé qui est associé à un taux d’attrition élevé laissant supposer des lacunes dans le modèle actuel. Nos publications antérieures suggèrent que la sensibilité in vitro de nos LC du CEO à la chimiothérapie carboplatin varie en 2D ou 3D. Il reste à élucider lequel de ces modèles est le plus représentatif de la réponse in vivo. De ce fait, nous avons émis l’hypothèse que le modèle 3D refléterait plus étroitement la sensibilité in vivo. L’objectif de cette étude était de caractériser la réponse au carboplatin de nos LC du CEO en monocouches et en sphéroïdes (3D), puis de les comparer à leur réponse in vivo (xénogreffes). Un total de 6 LC du CEO a été injecté dans des souris qui ont reçues trois différentes concentrations de carboplatin. Leurs réponses ont été évaluées/classées selon leurs mesures de volume tumoral et l’immunofluorescence. Ces mêmes LC ont été ensemencées dans des plaques à très faible adhérence pour former des sphéroïdes et les traiter. Des analyses de cytométrie en flux ont été effectuées afin de classer les LC selon leur concentration inhibitrice médiane (CI50). Nous avons comparé le tout aux résultats 2D (CI50) précédemment publiés. Nos résultats montrent que le système 3D démontre la meilleure concordance avec le modèle in vivo. Notamment, notre LC ultra-résistance en 2D devient plus sensible en modèle murin ou encore en 3D. Inversement, une LC ultra-sensible en 2D est plus résistante en xénogreffe et en sphéroïde. Les résultats découlant de notre étude sont importants à considérer lors d’investissement de temps et de fonds dans les études de criblage et de prédiction de réponses thérapeutiques.Epithelial ovarian adenocarcinoma (EOC) is the most lethal gynecological cancer. The drug discovery pipeline is heavily based on preclinical models. Typically, 2D cell line (CL)-based models are used to screen compounds followed by validation in animal models to generate the evidence needed to design clinical trials. This process incurs a high cost to the research pipeline and still results in high drug attrition rates. This may in part reflect the poor translation of preclinical to clinical results and points to deficiencies in modeling. Previous work from our laboratory shows that the sensitivity of our EOC CLs to carboplatin therapy varies between 2D and 3D in vitro models, however it is unclear how these differences align with the in vivo response. We hypothesize that 3D models will more closely reflect therapeutic in vivo response. The objective of this study was to characterize the carboplatin sensitivity of EOC CLs in 2D and 3D-spheroids and compare them to in vivo response using mouse xenografts. We injected mice with 6 different EOC CLs that were treated with 3 different carboplatin concentrations. Tumor volume measurements and immunofluorescence viability stains were used to categorize CLs by their sensitivity. The same CLs were seeded in low attachment plates to form, and thereafter treat, spheroids. Flow cytometry analysis was used to classify CLs by their 50% inhibitory response (IC50). The 2D response (IC50) for these CLs has previously been published. Our results show that therapeutic response changes significantly for a single CL between different systems, and the 3D model was most concordant with the in vivo model. Our ultra-resistant CL in 2D became more sensitive in 3D/mouse models. In contrast, the highly 2D sensitive CL became more resistant in our xenograft/spheroid models. The results are important to consider when investing time/funds in drug screening and therapeutic response prediction studies

“Freedom of speech requires actions” : Exploring the discourse of politicians convicted of hate‐speech against Muslims

This study explores how politicians convicted of hate‐speech against Muslims account for their actions in statements on their Facebook‐pages as well as in reported interviews. Taking a critical discursive psychological perspective, the study examines the strategies through which the politicians discursively claim and resist various subject positions, thus managing to construct their hate‐speech as everything from trivial mishaps to acts of virtue. The study examines the multifaceted dynamics of these constructions, and shows how elements from the Five Step Social Identity Model of the Development of Collective Hate are flexibly deployed in the discourse to serve distinct social and political purposes. By allowing the Social Identity and (critical) discursive approaches to challenge and develop each other, the study advances social psychological research on political communication and persuasion, and contributes to the debate on the boundaries between hate‐speech and freedom of speech.Peer reviewe

Progress on the implementation of Energy Performance Certificates in EU

Energy performance certificates (EPCs) are a key policy tool to inform about and to foster improvements to the energy performance of the building stock. Since their introduction in 2002 by the Energy Performance of Buildings Directive (EPBD), EPCs have been implemented across Member States (MSs) in different ways, depending on the political and legal context, the available technical capacities, as well as the characteristics of the buildings stock and buildings market in general. In 2021, in the context of ?Fit for 55? legislative package, the European Commission proposed the third revision of the EPBD. The proposal improves the provisions on EPCs, their issuing and display, and their databases. In particular, it pursues harmonisation across MSs through a mandatory template for EPCs and a harmonised scale of energy performance classes. This report presents the results of a survey conducted by JRC among MSs to collect information on how each MS has implemented the EPC scheme. It highlights differences among MSs regarding the energy uses included in the calculation, the floor area considered, the definition of energy classes, the main indicator(s), the number of EPCs issued, the availability of a national register, the mechanisms in place to ensure the quality of EPCs

Can households decrease their carbon dioxide emissions by consuming vegetables that are in season?

Climate change has become an increasingly topical subject. Recently debate on how our food affects the environment has flared. It has been shown that how the food we eat is grown and transported could be one the bigger contributors to the emission of carbon dioxide into the atmosphere. The aim of this study is to see how consumer's choices of vegetables affect release of carbon dioxide. The results show that emissions of carbon dioxide can be lowered by consuming vegetables that have been grown on open land. Vegetables that have to be grown in heated greenhouses in Sweden should perhaps be exchanged for such that have been grown in unheated greenhouses in southern Europe, even though the transport distance is significant.Klimatförändringarna har blivit ett alltmer aktuellt ämne. Under senare tid har debatterna kring hur vår mat påverkar miljön blossat upp. Det har visat sig att odling och transport av maten vi äter kan vara en av de större källorna till koldioxidutsläppen. Syftet med detta arbete är att studera hur konsumenternas val av färska grönsaker påverkar koldioxidutsläppen. Resultaten visar att om man konsumerar grönsaker som kan odlas på friland i Sverige minskar man utsläpp av koldioxid. Grönsaker som måste odlas i uppvärmda växthus i Sverige bör kanske bytas ut mot sådana som odlats i ouppvärmda växthus i södra Europa, trots den långa transporten

Reproduction and stress response endocrinology in blue (Balaenoptera musculus) and gray (Eschrichtius robustus) whales

Thesis (Ph.D.) University of Alaska Fairbanks, 2020Identification of biomarkers that reflect physiological status is fundamental for assessing population health, as well as providing more accurate estimates of life history parameters. Blue (Balaenoptera musculus) and gray (Eschrichtius robustus) whale populations feed on lower trophic levels and migrate between the eastern Tropical and the eastern North Pacific Ocean. With increasing disturbances (e.g., changing environment and human activities), understanding the stress response, resultant coping mechanisms, and the subsequent effects on reproduction, is of growing importance. While extensive knowledge is available on photo-identification and ecology of these two species, information on physiology is limited and what exists is outdated. This dissertation validated and measured a suite of steroid hormones in blubber tissue using an enzyme immunoassay technique to develop physiological biomarkers for reproduction and metabolism in these two species. Coupled with sighting history data, progesterone and testosterone were validated as biomarkers for reproductive physiology. In both species, progesterone concentrations were higher in pregnant females and mixture models were developed to estimate reproductive status for whales of unknown status. Testosterone showed greater variability in adult males and concentrations were higher in samples collected during fall, suggesting physiological preparation for mating. Additionally, progesterone concentrations in gray whales were higher in calves of both sexes, indicating maternal transfer through lactation, while in blue whales, testosterone was detectable only in males and in pregnant whales, suggesting its biosynthesis or metabolism is altered during gestation. Biomarkers for stress response were developed through analytical and biological validation of three corticosteroid hormones: cortisol, corticosterone and aldosterone. First, analytical validations (i.e., parallelism and accuracy tests) were used to determine detectability and measurement accuracy of these hormones using commercially available kits. Hormone concentrations were tested for any relationships with life history parameters (e.g., age and reproductive state) as well as with area and time of sampling within presumably "healthy" (biopsies) whales and "stressed" (stranded) whales. "Stressed" whales, especially those that perished due to trauma and/or nutritional stress, had higher concentrations of all three corticosteroid hormones than "healthy" whales, suggesting ongoing alteration of metabolic status due to a stress response. In female "healthy" whales, reproductive status appeared to be a major factor influencing corticosterone concentrations in blue whales and for cortisol in gray whales. Overall, cortisol was determined to be a valid marker for body conditions in both species. These results set a milestone for assisting to better understand the impact of a changing environment on the physiology of these species and can be used to develop more accurate reproductive and survival rates to use in population dynamics models for management of subsistence resources and for conservation of endangered species.Fulbright Scholarship, Alaska IDeA Network of Biomedical Research Excellence (INBRE) Graduate Research Award, University of Alaska Fairbanks (UAF), Calvin-Lensink Fellowship, and the UAF Graduate School Dissertation completion award, INBRE, Biomaedical Learning and students training (BLaST), Society of Marine Mammalogy, Bill Samara Research Award, the Goering Family Scholarship, Cascadia Research CollectiveGeneral introduction -- Chapter 1: Blubber endocrine profiles provide insights on reproductive biology in blue whales from the eastern North Pacific Ocean -- Chapter 2: The use of endocrine biomarkers to update information on gray whale reproductive physiology -- Chapter 3: Corticosteroid hormones as biomarkers for stress response in blubber of blue and gray whales -- General conclusion -- References: General introduction and conclusion

La presunta “neutralità” del diritto transnazionale dello sport

Sport has reached an economic and social dimension that has led top sports institutions, led by the IOC, to equip themselves with tools to preserve its autonomy. The Olympic Charter aims to achieve this goal through the principle of "political neutrality", according to which sports leaders often avoid taking a position on thorny "political" issues, which come to concern the protection of the athletes' fundamental rights, although the same rights appear at least underlying the Charter itself. This work, through a comparative survey that also reflects on the transnational sports law, aims to shed light on the possible contradiction of sports institutions, who struggle to combine the role of sport as a promoter of fundamental rights and social inclusion with the purely sporting (and economic) dimension of the same, which they try to keep away from political conditioning

The Covenant of Mayors: Evaluation of Sustainable Energy Action Plans from Eastern Partnership and Central Asian countries

Out of 5600 Sustainable Energy Action Plans (SEAPs) submitted to the Covenant of Mayors, about 100 SEAPS come from local authorities in Eastern Partnerships and Central Asian countries (CoM East). This report presents the results of the in depth evaluation of 14 SEAPs from CoM East countries, aimed at identifying good practices, but also weaknesses and challenges. The analysis has generally revealed a good compliance with the key commitments, in terms of definition of the target by 2020, calculation of the emission inventory, and definition of actions in the key sectors of activity. Aspects related to governance (e.g. the adaptation of administrative structures, the mobilisation of civil society, or the SEAP monitoring process) and to the financing of actions are often described in general terms, without presenting tailor-made strategies. Good practices identified in the 14 SEAPs are presented in the report.JRC.C.2-Energy Efficiency and Renewable