L'impact de l'écran d'ordinateur sur la relation médecin-patient dans les cabinets de médecine générale d'Ile-de-France : le point de vue du médecin

Introduction: The introduction of computers in physicians’ offices began in the early 1990’s and accelerated since 1999 because obligation was made for doctors to send their invoices electronically to the social security management system. The computer’s entrance in doctor’s office hence happened without any consideration on its possible impact on the doctor-patient relationship during consultation. We will focus on the impact of the computer screen as an interfering object in the relationship.Method: This is a cross-sectional descriptive quantitative non-probabilistic study led in general practitioners’ offices in the Paris region with an online self-administered questionnaire from September to November 2015.Results: Screen content was not visible for the patient in 71% of cases. 2/3 of the doctors would prefer a different configuration of their desktop. 84% used their computer screen to educate patients. 70% claimed looking at their screen less than 30% of the time. Women spent significantly more time looking at it. Time spent looking at the screen was considered too important for 23% and more particularly for the 25-30 year-old doctors. The average grade for the impact of the screen on the relationship was rated +0,603 [±2,350].Discussion: In our study, computer screen appears well integrated in the consultation, but doctors don’t seem fully aware of all sides of its impact. To reduce the inconvenience the screen causes to the relationship, the main actions would be: a rotating screen used to educate patients, computer typing at appropriate moments, keeping an eye contact with the patient.Introduction : L’informatisation des cabinets médicaux, initiée au début des années 1990, s’est accélérée à partir de 1999 suite à l’obligation faite aux médecins libéraux de télétransmettre les feuilles de soins. L’irruption de l’ordinateur au sein du cabinet s’est donc faite sans réflexion sur son impact éventuel dans la relation médecin-patient au cours de la consultation. Nous nous intéresserons plus particulièrement à l’impact de l’écran en tant qu’objet interférant dans la relation.Matériel et méthode : Il s’agit d’une étude transversale descriptive quantitative non probabiliste menée dans des cabinets ambulatoires de médecine générale d’Ile de France par auto-questionnaire en ligne de septembre à novembre 2015.Résultats : Le contenu de l’écran n’était pas visible du patient dans 71% des cas. Les 2/3 des médecins préfèreraient une configuration de leur bureau différente. 84% déclaraient utiliser leur écran dans un but éducatif. 70% des médecins estimaient regarder l’écran moins de 30% du temps, les femmes regardant significativement plus leur écran. Le temps consacré à l’écran paraissait trop important pour 23% d’entre eux et plus particulièrement pour les 25-30 ans. L’impact global moyen de l’écran sur la relation était coté +0,603 [±2,350].Discussion : L’écran est bien intégré dans la consultation mais les médecins de notre étude ne semblent pas conscients de toutes les facettes de son impact. Pour diminuer les inconvénients, les principales mesures seraient: un écran mobile, utilisé à but éducatif, une saisie sur clavier aux moments appropriés, le maintien d’un contact visuel avec le patient

Eradication of chemoresistant cancer cells overexpressing the drug transporter MRP1 using activators of GSH efflux through MRP1

Le transporteur de drogues membranaire MRP1 participe à la résistance des cellules cancéreuses à la chimiothérapie lorsqu’il est surexprimé. Cette surexpression peut être exploitée afin de provoquer l’apoptose sélective de ces cellules, MRP1 devenant leur talon d’Achille : c’est l’effet de sensibilité collatérale (SC). Ainsi, le vérapamil stimule l’efflux médié par MRP1 d’un tripeptide antioxydant indispensable aux cellules, le GSH ou glutathion réduit, et provoque la mort sélective des cellules surexprimant ce transporteur. La recherche d’autres agents de SC comme le vérapamil nous a menés à l’étude de composés flavonoïdiques pouvant induire un efflux rapide et massif de GSH. Parmi ces composés, nous avons identifié un puissant agent de SC des cellules résistantes surexprimant MRP1, le dimère de flavonoïde 4e, candidat très prometteur pour de futures études in vivo. Nous avons déterminé que la surexpression de MRP1 est effectivement responsable de la SC dans les cellules cancéreuses résistantes H69AR, et que l’efflux de GSH se doit d’être massif et prolongé pour induire l’apoptose des cellules. Nous avons montré que cet efflux perturbe l’homéostasie du glutathion et l’état redox des cellules, entraînant un stress oxydatif qui participe au déclenchement de la mort cellulaire. Enfin, nous nous sommes attachés à identifier d’éventuelles cibles secondaires des agents de SC dans les cellules surexprimant MRP1, via l’initiation de l’étude de leur transcriptome et métabolome. La compréhension du mécanisme d’action de ces agents de sensibilité collatérale vise, à terme, à l’éradication des cancers résistants surexprimant MRP1The membrane drug transporter MRP1 is involved in the resistance of cancer cells to chemotherapy, when overexpressed. This overexpression can be exploited in order to induce the selective apoptosis of these cells, so that MRP1 becomes their Achilles’ heel: this is called Collateral Sensitivity (CS). Thus verapamil stimulates the MRP1-mediated efflux of GSH (reduced form of glutathione) that is an antioxidant tripeptide essential for cells, and induces the selective death of MRP1- overexpressing cells. Seeking for other CS agents than verapamil led to the study of flavonoid compounds able to induce a massive and rapid efflux of GSH and to the identification of a powerful CS agent of resistant cells overexpressing MRP1, i.e. flavonoid dimer 4e, which is a very promising candidate for in vivo studies. We determined that overexpression of MRP1 is indeed responsible for CS in H69AR resistant cancer cells, and that GSH efflux must be massive and protracted in order to induce cell apoptosis. We showed that this efflux disturbs glutathione homeostasis and cell redox state, which leads to an oxidative stress that is involved in triggering cell death. At last, we sought to identify possible secondary targets of CS agents in MRP1-overexpressing cells, via the initiation of transcriptomic and metabolomic studies. Understanding the mechanism of action of these Collateral Sensitivity agents aims to the eradication of resistant cancers that overexpress MRP

MRP1-dependent Collateral Sensitivity of Multidrug-resistant Cancer Cells: Identifying Selective Modulators Inducing Cellular Glutathione Depletion

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Molecular analysis of the massive GSH transport mechanism mediated by the human Multidrug Resistant Protein 1/ABCC1

International audienceThe transporter Multidrug Resistance Protein 1 (MRP1, ABCC1) is implicated in multidrug resistant (MDR) phenotype of cancer cells. Glutathione (GSH) plays a key role in MRP1 transport activities. In addition, a ligand-stimulated GSH transport which triggers the death of cells overexpressing MRP1, by collateral sensitivity (CS), has been described. This CS could be a way to overcome the poor prognosis for patients suffering from a chemoresistant cancer. The molecular mechanism of such massive GSH transport and its connection to the other transport activities of MRP1 are unknown. In this context, we generated MRP1/MRP2 chimeras covering different regions, MRP2 being a close homolog that does not trigger CS. The one encompassing helices 16 and 17 led to the loss of CS and MDR phenotype without altering basal GSH transport. Within this region, the sole restoration of the original G1228 (D1236 in MRP2) close to the extracellular loop between the two helices fully rescued the CS (massive GSH efflux and cell death) but not the MDR phenotype. The flexibility of that loop and the binding of a CS agent like verapamil could favor a particular conformation for the massive transport of GSH, not related to other transport activities of MRP1

Flavonoid dimers are highly potent killers of multidrug resistant cancer cells overexpressing MRP1

International audienceMRP1 overexpression in multidrug-resistant cancer cells has been shown to be responsible for collateral sensitivity to some flavonoids that stimulate a huge MRP1-mediated GSH efflux. This massive GSH depletion triggers the death of these cancer cells. We describe here that bivalent flavonoid dimers strikingly stimulate such MRP1-mediated GSH efflux and trigger a 50-100 fold more potent cell death than their corresponding monomers. This selective and massive cell death of MRP1-overexpressing cells (both transfected and drug-selected cell lines) is no longer observed either upon catalytic inactivation of MRP1 or its knockdown by siRNA. The best flavonoid dimer, 4e, kills MRP1-overexpressing cells with a selective ratio higher than 1000 compared to control cells and an EC 50 value of 0.1 lM, so far unequaled as a collateral sensitivity agent targeting ABC transporters. This result portends the flavonoid dimer 4e as a very promising compound to appraise in vivo the therapeutic potential of collateral sensitivity for erad-ication of MRP1-overexpressing chemoresistant cancer cells in tumors