Implicating the mechanisms of ADP-ribosylation factor activation in the resistance of invasive breast cancer cells to EGFR tyrosine kinase inhibitors

ADP-ribosylation factor-1 (ARF1) est une petite GTPase principalement connue pour son rôle dans la formation de vésicules au niveau de l’appareil de Golgi. Récemment, dans des cellules de cancer du sein, nous avons démontré qu’ARF1 est aussi un médiateur important de la signalisation du récepteur du facteur de croissance épidermique (EGFR) contrôlant la prolifération, la migration et l'invasion cellulaire. Cependant, le mécanisme par lequel l’EGFR active la GTPase ainsi que le rôle de cette dernière dans la régulation de la fonction du récepteur demeure inconnue. Dans cette thèse, nous avions comme objectifs de définir le mécanisme d'activation de ARF1 dans les cellules de cancer du sein hautement invasif et démontrer que l’activation de cette isoforme de ARF joue un rôle essentiel dans la résistance de ces cellules aux inhibiteurs de l'EGFR. Nos études démontrent que les protéines d’adaptatrices Grb2 et p66Shc jouent un rôle important dans l'activation de ARF1. Alors que Grb2 favorise le recrutement d’ARF1 à l'EGFR ainsi que l'activation de cette petite GTPase, p66Shc inhibe le recrutement du complexe Grb2-ARF1 au récepteur et donc contribue à limiter l’activation d’ARF1. De plus, nous démontrons que ARF1 favorise la résistance aux inhibiteurs des tyrosines kinases dans les cellules de cancer du sein hautement invasif. En effet, une diminution de l’expression de ARF1 a augmenté la sensibilité descellules aux inhibiteurs de l'EGFR. Nous montrons également que de hauts niveaux de ARF1 contribuent à la résistance des cellules à ces médicaments en améliorant la survie et les signaux prolifératifs à travers ERK1/2, Src et AKT, tout en bloquant les voies apoptotiques (p38MAPK et JNK). Enfin, nous mettons en évidence le rôle de la protéine ARF1 dans l’apoptose en réponse aux traitements des inhibiteurs de l’EGFR. Nos résultats indiquent que la dépletion d’ARF1 promeut la mort cellulaire induite par gefitinib, en augmentant l'expression de facteurs pro-apoptotiques (p66shc, Bax), en altérant le potentiel de la membrane mitochondriale et la libération du cytochrome C. Ensemble, nos résultats délimitent un nouveau mécanisme d'activation de ARF1 dans les cellules du cancer du sein hautement invasif et impliquent l’activité d’ARF1 comme un médiateur important de la résistance aux inhibiteurs EGFR.

Historic turning point or just another chapter? The results of a foreign-policy summit. EPC Post-Summit Analysis, 24 March 2014

The March 2014 European Council could enter the history books as a turning point, not only in the EU’s relations with Russia but also in its role as a foreign policy actor. Events in Ukraine inevitably dominated the Summit, with EU leaders adopting a balanced approach aimed at achieving three key objectives – de-escalation, containment/deterrence and cooperation – based on political and economic support for Ukraine, increased but limited pressure on Russia, and moves to strengthen ties with other EU neighbours. The Summit also discussed a range of economic and environmental policy issues, with the situation in Ukraine casting a long shadow over the discussion on energy policy, but failed to reach agreement on the EU’s climate goals to 2030, or to put more flesh on the bones of calls for a European “industrial renaissance”. However, two other developments were particularly significant: the creation of the second pillar of the future banking union, establishing a single regime for winding down failing banks; and changes to the savings tax directive, bringing years of negotiation to an end.

A historic reminder, an ever-present dilemma? - Assessing Brexit’s potential consequences for European security. EPC Commentary, 18 May 2016

On 9 May 2016, in a further attempt to discourage the British public opinion from opting for their country’s abandonment of the European Union (EU) in the ‘in/out’ referendum on 23 June, Prime Minister David Cameron stated that the UK has regretted "turning its back" on Europe in the past, and that the EU had "helped reconcile" countries and maintain peace on the Old Continent.

Historic records of organic compounds from a high Alpine glacier: influences of biomass burning, anthropogenic emissions, and dust transport

Historic records of α-dicarbonyls (glyoxal, methylglyoxal), carboxylic acids (C6–C12 dicarboxylic acids, pinic acid, p-hydroxybenzoic acid, phthalic acid, 4-methylphthalic acid), and ions (oxalate, formate, calcium) were determined with annual resolution in an ice core from Grenzgletscher in the southern Swiss Alps, covering the time period from 1942 to 1993. Chemical analysis of the organic compounds was conducted using ultra-high-performance liquid chromatography (UHPLC) coupled to electrospray ionization high-resolution mass spectrometry (ESI-HRMS) for dicarbonyls and long-chain carboxylic acids and ion chromatography for short-chain carboxylates. Long-term records of the carboxylic acids and dicarbonyls, as well as their source apportionment, are reported for western Europe. This is the first study comprising long-term trends of dicarbonyls and long-chain dicarboxylic acids (C6–C12) in Alpine precipitation. Source assignment of the organic species present in the ice core was performed using principal component analysis. Our results suggest biomass burning, anthropogenic emissions, and transport of mineral dust to be the main parameters influencing the concentration of organic compounds. Ice core records of several highly correlated compounds (e.g., p-hydroxybenzoic acid, pinic acid, pimelic, and suberic acids) can be related to the forest fire history in southern Switzerland. P-hydroxybenzoic acid was found to be the best organic fire tracer in the study area, revealing the highest correlation with the burned area from fires. Historical records of methylglyoxal, phthalic acid, and dicarboxylic acids adipic acid, sebacic acid, and dodecanedioic acid are comparable with that of anthropogenic emissions of volatile organic compounds (VOCs). The small organic acids, oxalic acid and formic acid, are both highly correlated with calcium, suggesting their records to be affected by changing mineral dust transport to the drilling site.

Herbert Hoover national historic site, interpretive prospectus (1971) B1; Natural resources management plan (1980) B2; Cultural resources management plan (1981) B3; Annual statement for interpretation and visitor services B4; Snowmobile use, environmental assessment (EA) : environmental impact statement.

Mode of access: Internet.

Performance of historic stone building materials and systems : observations by architects, engineers and building conservators : excerpts from workshop discussions held on August 10, 1987, funded by the U.S. Environmental Protection Agency and the U.S. Department of the Interior, National Park Service, Cultural Resources Acid Rain Research Program.

"June 1988."

Historic preservation resources /

Mode of access: Internet.

National Park Service concessions management : hearings before the Subcommittee on National Parks, Historic Preservation, and Recreation of the Committee on Energy and Natural Resources, United States Senate, One Hundred Seventh Congress, first session to review the National Park Service implementation of management policies and procedures to comply with the provisions of Titles I, II, III, IV, V, VI, VII, and VIII of the National Parks Omnibus Management Act of 1998, March 22, 2001, March 29, 2001.

Shipping list no.: 2001-0261-P.

Fure's cabin, Bay of Islands, Naknek Lake, Katmai National Park & Preserve : historic structure report /

Cover title: Fure's cabin : historic structure report, Katmai National Park & Preserve.

The Harry S. Truman Library in historic Independence.

Mode of access: Internet.

San Diego region historic wave and sea level data report : Coast of California Storm and Tidal Waves Study /

Mode of access: Internet.

Jew and Mormon; historic group relations and religious outlook.

Mode of access: Internet.