The Spanish Right and the Jews (1898-1945)

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Perpetrator Characteristics of Azole Antifungal Drugs on Three Oral Factor Xa Inhibitors Administered as a Microdosed Cocktail

Background!#!Factor Xa inhibitors (FXaIs) are increasingly used without having sufficient drug-drug interaction data. Using a microdosed cocktail methodology could support filling the knowledge gap quickly.!##!Methods!#!In a randomised crossover trial, we investigated the drug-drug interactions between six oral azole antifungals and a microdosed FXaI cocktail containing 25 µg rivaroxaban, 25 µg apixaban, and 50 µg edoxaban. Additionally, different enzyme activities were also monitored using a microdosed cocktail approach. The six different azole antifungals were administered in therapeutic doses over a 24 h period, while the microdosed cocktails were administered 1 h after administration of the azole antifungals.!##!Results!#!Ketoconazole and posaconazole were the strongest perpetrators, showing similar increases as apixaban (area under the concentration-time curve ratio [AUCR] 1.64 and 1.62, respectively) and edoxaban (AUCR 2.08 and 2.1, respectively), whereas ketoconazole increased rivaroxaban 2.32-fold but only increased posaconazole 1.37-fold. All other azole antifungals showed less perpetrator effects on the FXaIs. Cytochrome P450 (CYP) 3A inhibition was confirmed using microdosed midazolam, with ketoconazole also the most potent perpetrator (8.42-fold).!##!Conclusion!#!Drug-drug interactions for three victim drugs of the same drug class (FXaIs) with different clearance mechanisms can be studied using a microdosed cocktail approach. Using members of the azole antifungal drug class as perpetrators, multiple interactions can be studied in one trial, and a more detailed insight into the underlying interaction mechanisms is possible.!##!Clinical trial registration!#!EudraCT number: 2017-004453-16

CDX2 controls genes involved in the metabolism of 5-fluorouracil and is associated with reduced efficacy of chemotherapy in colorectal cancer

Most patients affected with colorectal cancers (CRC) are treated with 5-fluorouracil (5-FU)-based chemotherapy but its efficacy is often hampered by resistance mechanisms linked to tumor heterogeneity. A better understanding of the molecular determinants involved in chemoresistance is critical for precision medicine and therapeutic progress. Caudal type homeobox 2 (CDX2) is a master regulator of intestinal identity and acts as tumor suppressor in the colon. Here, using a translational approach, we examined the role of CDX2 in CRC chemoresistance. Unexpectedly, we discovered that the prognosis value of CDX2 for disease-free survival of patients affected with CRC is lost upon chemotherapy and that CDX2 expression enhances resistance of colon cancer cells towards 5-FU. At the molecular level, we found that CDX2 expression correlates with higher levels of genes regulating the bioavailability of 5-FU through efflux (ABCC11) and catabolism (DPYD) in patients affected with CRC and CRC cell lines. We further showed that CDX2 directly regulates the expression of ABCC11 and that the inhibition of ABCC11 improves 5-FU-sensitivity of CDX2-expressing colon cancer cells. Thus, this study illustrates how biological functions are hijacked in CRC cells and reveals the therapeutic interest of CDX2/ABCC11/DPYD to improve systemic chemotherapy in CRC

Entre Mots et marbre. Les métamorphoses d’Auguste

International audienceThe success of the sumptuous exhibition “Moi, Auguste, empereur de Rome...”, which was organised in Paris in 2014 for the bi-millennium of the princeps’ death, shows that Octavian-Augustus, who founded the principate while defending the cause of liberty and res publica, is still nowadays fascinating people. Yet, concurrently with the official iconography, literature gives valued testimonies on the political, legal, moral, social, and cultural ambivalence which depicts the prince’s action and the set up of the new regime. But, even if they have been lucid witnesses of their time, Vergil, Horace, Ovid, Livy, and the other writers played also a crucial part in the renewing of artistic forms and in the drawing up of a new political imagery. The articles collected in this volume, which originates from the symposium “Augustus in words”, organised in the wake of the Parisian exhibition, focus on the relationship – sometimes harmonious, sometimes conflicting, but always ambivalent – between Politics and Literature, around Augustus’ image.Le succès remporté par la somptueuse exposition “Moi, Auguste, empereur de Rome…”, qui s’est tenue au Grand Palais en 2014 à l’occasion du bimillénaire de la mort du princeps, témoigne de la fascination exercée, aujourd’hui encore, par Octave-Auguste,qui fut le fondateur du principat tout en se présentant comme le défenseur des libertés et le restaurateur de la res publica. Or, parallèlement à l’iconographie officielle, la littérature offre un précieux témoignage sur les ambiguïtés politiques, juridiques,morales, sociales et culturelles qui caractérisent l’action du prince et la mise en place du nouveau régime. Cependant, pour être des témoins lucides de leur temps, Virgile, Horace, Ovide, Tite-Live et les autres n’en furent pas moins des acteurs influents,qui contribuèrent non seulement au renouvellement des formes artistiques, mais à l’élaboration d’un nouvel imaginaire politique. Les contributions rassemblées dans le présent volume, qui est issu du colloque “Auguste en mots”, organisé dans le sillage de l’exposition parisienne examinent la relation – tantôt harmonieuse, tantôt conflictuelle, mais toujours ambigüe – entre sphère politique et sphère littéraire autour de l’image d’Auguste

Entre Mots et marbre. Les métamorphoses d’Auguste

International audienceThe success of the sumptuous exhibition “Moi, Auguste, empereur de Rome...”, which was organised in Paris in 2014 for the bi-millennium of the princeps’ death, shows that Octavian-Augustus, who founded the principate while defending the cause of liberty and res publica, is still nowadays fascinating people. Yet, concurrently with the official iconography, literature gives valued testimonies on the political, legal, moral, social, and cultural ambivalence which depicts the prince’s action and the set up of the new regime. But, even if they have been lucid witnesses of their time, Vergil, Horace, Ovid, Livy, and the other writers played also a crucial part in the renewing of artistic forms and in the drawing up of a new political imagery. The articles collected in this volume, which originates from the symposium “Augustus in words”, organised in the wake of the Parisian exhibition, focus on the relationship – sometimes harmonious, sometimes conflicting, but always ambivalent – between Politics and Literature, around Augustus’ image.Le succès remporté par la somptueuse exposition “Moi, Auguste, empereur de Rome…”, qui s’est tenue au Grand Palais en 2014 à l’occasion du bimillénaire de la mort du princeps, témoigne de la fascination exercée, aujourd’hui encore, par Octave-Auguste,qui fut le fondateur du principat tout en se présentant comme le défenseur des libertés et le restaurateur de la res publica. Or, parallèlement à l’iconographie officielle, la littérature offre un précieux témoignage sur les ambiguïtés politiques, juridiques,morales, sociales et culturelles qui caractérisent l’action du prince et la mise en place du nouveau régime. Cependant, pour être des témoins lucides de leur temps, Virgile, Horace, Ovide, Tite-Live et les autres n’en furent pas moins des acteurs influents,qui contribuèrent non seulement au renouvellement des formes artistiques, mais à l’élaboration d’un nouvel imaginaire politique. Les contributions rassemblées dans le présent volume, qui est issu du colloque “Auguste en mots”, organisé dans le sillage de l’exposition parisienne examinent la relation – tantôt harmonieuse, tantôt conflictuelle, mais toujours ambigüe – entre sphère politique et sphère littéraire autour de l’image d’Auguste

Entre Mots et marbre. Les métamorphoses d’Auguste

International audienceThe success of the sumptuous exhibition “Moi, Auguste, empereur de Rome...”, which was organised in Paris in 2014 for the bi-millennium of the princeps’ death, shows that Octavian-Augustus, who founded the principate while defending the cause of liberty and res publica, is still nowadays fascinating people. Yet, concurrently with the official iconography, literature gives valued testimonies on the political, legal, moral, social, and cultural ambivalence which depicts the prince’s action and the set up of the new regime. But, even if they have been lucid witnesses of their time, Vergil, Horace, Ovid, Livy, and the other writers played also a crucial part in the renewing of artistic forms and in the drawing up of a new political imagery. The articles collected in this volume, which originates from the symposium “Augustus in words”, organised in the wake of the Parisian exhibition, focus on the relationship – sometimes harmonious, sometimes conflicting, but always ambivalent – between Politics and Literature, around Augustus’ image.Le succès remporté par la somptueuse exposition “Moi, Auguste, empereur de Rome…”, qui s’est tenue au Grand Palais en 2014 à l’occasion du bimillénaire de la mort du princeps, témoigne de la fascination exercée, aujourd’hui encore, par Octave-Auguste,qui fut le fondateur du principat tout en se présentant comme le défenseur des libertés et le restaurateur de la res publica. Or, parallèlement à l’iconographie officielle, la littérature offre un précieux témoignage sur les ambiguïtés politiques, juridiques,morales, sociales et culturelles qui caractérisent l’action du prince et la mise en place du nouveau régime. Cependant, pour être des témoins lucides de leur temps, Virgile, Horace, Ovide, Tite-Live et les autres n’en furent pas moins des acteurs influents,qui contribuèrent non seulement au renouvellement des formes artistiques, mais à l’élaboration d’un nouvel imaginaire politique. Les contributions rassemblées dans le présent volume, qui est issu du colloque “Auguste en mots”, organisé dans le sillage de l’exposition parisienne examinent la relation – tantôt harmonieuse, tantôt conflictuelle, mais toujours ambigüe – entre sphère politique et sphère littéraire autour de l’image d’Auguste

Influence of stress on fear memory processes in an aversive differential conditioning paradigm in humans

It is widely assumed that learning and memory processes play an important role in the pathogenesis, expression, maintenance and therapy of anxiety disorders, such as phobias or post-traumatic stress disorder (PTSD). Memory retrieval is involved in symptom expression and maintenance of these disorders, while memory extinction is believed to be the underlying mechanism of behavioral exposure therapy of anxiety disorders. There is abundant evidence that stress and stress hormones can reduce memory retrieval of emotional information, whereas they enhance memory consolidation of extinction training. In this study we aimed at investigating if stress affects these memory processes in a fear conditioning paradigm in healthy human subjects. On day 1, fear memory was acquired through a standard differential fear conditioning procedure. On day 2 (24h after fear acquisition), participants either underwent a stressful cold pressor test (CPT) or a control condition, 20min before memory retrieval testing and extinction training. Possible prolonged effects of the stress manipulation were investigated on day 3 (48h after fear acquisition), when memory retrieval and extinction were tested again. On day 2, men in the stress group showed a robust cortisol response to stress and showed lower unconditioned stimulus (US) expectancy ratings than men in the control group. This reduction in fear memory retrieval was maintained on day 3. In women, who showed a significantly smaller cortisol response to stress than men, no stress effects on fear memory retrieval were observed. No group differences were observed with respect to extinction. In conclusion, the present study provides evidence that stress can reduce memory retrieval of conditioned fear in men. Our findings may contribute to the understanding of the effects of stress and glucocorticoids on fear symptoms in anxiety disorders and suggest that such effects may be sex-specific

Trastuzumab treatment beyond progression in advanced breast cancer : patterns of care in six Swiss breast cancer centers

Trastuzumab is an established treatment for HER2-positive breast cancer (BC). We analyzed Swiss patterns of care in patients with HER2-positive BC after disease progression on trastuzumab-containing therapy for metastatic BC (MBC)