Les accords de Bled : la France, la Petite Entente et l'attribution de l'égalité des droits à la Hongrie (septembre 1937-octobre 1938)

International audienceDans le contexte général de la fin des années trente, l’attribution de l’égalité des droits à la Hongrie, et donc l’autorisation donnée à son réarmement, se pose certes de façon secondaire mais néanmoins avec une acuité nouvelle. Justement fondée, au début des années vingt, pour parer au danger hongrois, la Petite Entente, confrontée à l’inéluctable progression de l’influence de Berlin, n’a plus d’autres choix que de dépasser ses attributions premières et tenter de rallier à ses vues le gouvernement de Budapest, tout à la fois inquiet des menées allemandes dans la région danubienne et intéressé à tirer profit de l’évolution du rapport de force européen, notamment quant au statut de ses minorités nationales. La France, partisane de la constitution d’un bloc solide capable de tenir tête au Führer, soutient dans la mesure du possible les initiatives en ce sens. Mais ce faisant, les États parties ne font-ils pas un marché de dupes au terme duquel, sous couvert de garantir la paix européenne, chacun ambitionne de tirer la couverture à lui et d’assurer sa propre sécurité, quitte à parvenir à ses fins au détriment des autres

Les lieux du politique en Europe médiane (XIXe-XXe siècles) : introduction

Ce dossier consacré aux lieux du politique dans l’Europe médiane des XIXe et XXe siècles entend questionner, sur la longue durée, les modalités de politisation des espaces. Il interroge la pluralisation progressive de ces « lieux du politique » ainsi que les formes et les évolutions de leur appropriation par les acteurs, au regard des grandes scansions chronologiques qui structurent l’histoire contemporaine de la région considérée.Dedicated to the sites of politics of Central Europe in the 19th and 20th centuries, this special issue will investigate how spaces are politicized over the long term. It will also examine the progressive pluralization of these “sites of politics,” as well as the form and evolution of their appropriation by various actors, with regard to the major chronological moments that punctuated the contemporary history of the region in question

Les 100 ans du procès Villain : Paul-Boncour, avocat de Jaurès

Le 24 mars 1919, il y a tout juste un siècle, s'ouvrait le procès de l'assassin de Jean Jaurès, Raoul Villain, devant la Cour d'assises de la Seine. L'analyse du procès et de son déroulement permet d'appréhender les mutations politiques à l'oeuvre, notamment à gauche, dans la France d'après Grande Guerre. L'échec de la stratégie de la partie civile s'explique par les tiraillements très sévères qui affectent le parti socialiste et qui s'exacerbent à son issue. Dans ce contexte, une personnalité joue un rôle tout à fait singulier : Joseph Paul-Boncour, avocat principal de la partie civile lors du procès Villain

Joseph Paul-Boncour et l’héritage jaurésien

Paru dans " Notes de la Fondation Jean Jaurès"Le 29 mars 1919, le procès de Raoul Villain s'achève par l'acquittement de l'assassin de Jaurès. À l'issue de ce rendez-vous judiciaire et médiatique, l'avocat principal de la partie civile Joseph Paul-Boncour, ancien député du Loir-et-Cher (1909-1914) et ancien ministre du Travail (1911), alors tout juste revenu du front où il a passé les quatre années de guerre, s'impose comme un des premiers gardiens du temple jaurésien. Malgré l'échec de sa stratégie de défense, il trouve dans cette position matière à accumuler un certain capital politique au bénéfice d'une influence à conquérir au sein de la SFIO qu'il a rejoint en 1916

Prévention des effets secondaires de l'oxaliplatine par une approche pharmacogénétique

L oxaliplatine est un agent anticancéreux à marge thérapeutique étroite, principalement administré en traitement d un cancer du colon, rectum ou du pancréas, et dont la toxicité limitante est une neuropathie périphérique. En vue de prévenir cet effet indésirable, nous avons étudié la possible corrélation entre la présence des mutations A1142G et C154T sur le gène codant l alanine:glyoxylate aminotransférase (AGXT), et l apparition de neurotoxicités périphériques au cours d un traitement par oxaliplatine. Un déficit fonctionnel de cet enzyme qui transforme le glyoxylate en glycine, conséquence possible des mutations citées précédemment, pourrait engendrer une accumulation d oxalate dans l organisme et, par suite des neurotoxicités aiguës. Les résultats obtenus lors de cette étude n ont pas permis d établir un lien significatif entre ces deux phénomènes. Cependant, le caractère subjectif de l évaluation des neuropathies fut souligné, traduisant la nécessité d un examen neurologique précis voire d un électromyogramme, mais aussi l intérêt des travaux de protéomique en amont de l approche pharmacogénétique.Oxaliplatin is an antineoplasic drug with a narrow therapeutic window, mostly used in the treatment of rectum, colon or pancreas cancer, and which often lead to peripheral neurotoxicity. In order to prevent from this side effect, we have studied the hypothetic correlation between mutations A1142G and C154T on Alanine:Glyoxylate aminotransferase gene, and onset of neuropathies. A functional deficiency of this enzyme which is responsible of the transformation of glyoxylate to glycin, induced by these genetic mutations, would result in an accumulation of oxalate and, then, in the occurrence of neurotoxicity. Conclusions of this study did not demonstrate any significant link between these two phenomenons. Nonetheless, subjectivity of neurotoxicty evaluation was hardly shown, resulting in requirement of accurate examination, even an electromyography. Also, proteomic approach seems to be very useful upstream to pharmacogenomics.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Individual Fluorouracil Dose Adjustment in FOLFOX Based on Pharmacokinetic Follow-Up Compared With Conventional Body-Area-Surface Dosing: A Phase II, Proof-of-Concept Study

BackgroundTo compare the efficacy and safety of pharmacokinetically (PK) guided fluorouracil (5-FU) dose adjustment vs. standard body-surface-area (BSA) dosing in a FOLFOX (folinic acid, fluorouracil, oxaliplatin) regimen in metastatic colorectal cancer (mCRC). Patients And Methods A total of 118 patients with mCRC were administered individually determined PK-adjusted 5-FU in first-line FOLFOX chemotherapy. The comparison arm consisted of 39 patients, and these patients were also treated with FOLFOX with 5-FU by BSA. For the PK-adjusted arm 5-FU was monitored during infusion, and the dose for the next cycle was based on a dose-adjustment chart to achieve a therapeutic area under curve range (5-FUODPM Protocol). Results The objective response rate was 69.7% in the PK-adjusted arm, and median overall survival and median progression-free survival were 28 and 16 months, respectively. In the traditional patients who received BSA dosage, objective response rate was 46%, and overall survival and progression-free survival were 22 and 10 months, respectively. Grade 3/4 toxicity was 1.7% for diarrhea, 0.8% for mucositis, and 18% for neutropenia in the dose-monitored group; they were 12%, 15%, and 25%, respectively, in the BSA group. Conclusions Efficacy and tolerability of PK-adjusted FOLFOX dosing was much higher than traditional BSA dosing in agreement with previous reports for 5-FU monotherapy PK-adjusted dosing. Analysis of these results suggests that PK-guided 5-FU therapy offers added value to combination therapy for mCRC

In Vitro Stability of Low-Concentration Ziconotide Alone or in Admixtures in Intrathecal Pumps

ObjectivesZiconotide is often administered in combination with other analgesics via an intrathecal pump. Studies have established that ziconotide is stable when delivered alone in high concentrations. No stability data are available, however, for ziconotide given in low concentrations and/or with other analgesics as usually occurs in clinical oncology practice. The objective of this study was to assess the in vitro stability of ziconotide alone and combined with other analgesics in intrathecal pumps at 37°C, as well as in syringes at 5°C, to evaluate conditions for storing and transporting preparations. Materials and Methods Various ziconotide concentrations (0.1, 0.25, 0.5, and 0.75 μg/mL) were combined with an admixture of ropivacaine (7.5 mg/mL), morphine (7.5 mg/mL), and clonidine (15 μg/mL) in 20-mL intrathecal pumps at 37°C and in syringes at 5°C. Solutions of ziconotide alone in concentrations of 0.25, 0.5, 0.75, and 1 μg/mL were introduced into pumps at 37°C and syringes at 5°C. Assays were performed using ultra high pressure liquid chromatography. Results In admixtures, mean ziconotide concentrations decreased linearly to 53.4% (±3.33%) of baseline after 35 days. When ziconotide was introduced alone in pumps at 37°C, the residual concentration on day 31 was 35.54% (±0.04%) with 0.25 μg/mL, 39.37% (±0.15%) with 0.5 μg/mL, and 44.49% (±0.18%) with 1 μg/mL. Ziconotide alone or combined with the other analgesics was stable in syringes stored at 5°C. The preparations complied with the prescriptions, with a mean error of less than 10%, except with the lowest ziconotide concentration (0.1 μg/mL). Conclusions At the low ziconotide concentrations studied, the degradation of ziconotide admixed with other drugs was linear and only weakly influenced by the baseline concentration. Linear regression with intrapolation to 30 days showed that the degradation of ziconotide admixed with other drugs was consistent with previously published data

Irinotecan induces steroid and xenobiotic receptor (SXR) signaling to detoxification pathway in colon cancer cells

<p>Abstract</p> <p>Background</p> <p>Resistance to chemotherapy remains one of the principle obstacles to the treatment of colon cancer. In order to identify the molecular mechanism of this resistance, we investigated the role of the steroid and xenobiotic receptor (SXR) in the induction of drug resistance. Indeed, this nuclear receptor plays an important role in response to xenobiotics through the upregulation of detoxification genes. Following drug treatments, SXR is activated and interacts with the retinoid X receptor (RXR) to induce expression of some genes involved in drug metabolism such as phase I enzyme (like CYP), phase II enzymes (like UGT) and transporters (e.g. MDR1).</p> <p>Results</p> <p>In this study, we have shown that endogenous SXR is activated in response to SN-38, the active metabolite of the anticancer drug irinotecan, in human colon cancer cell lines. We have found that endogenous SXR translocates into the nucleus and associates with RXR upon SN-38 treatment. Using ChIP, we have demonstrated that endogenous SXR, following its activation, binds to the native promoter of the CYP3A4 gene to induce its expression. RNA interference experiments confirmed SXR involvement in CYP3A4 overexpression and permitted us to identify CYP3A5 and MRP2 transporter as SXR target genes. As a consequence, cells overexpressing SXR were found to be less sensitive to irinotecan treatment.</p> <p>Conclusions</p> <p>Altogether, these results suggest that the SXR pathway is involved in colon cancer irinotecan resistance in colon cancer cell line via the upregulation of select detoxification genes.</p

Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers