Noninvasive Assessment of Atrial Fibrillation Complexity in Relation to Ablation Characteristics and Outcome

Background: The use of surface recordings to assess atrial fibrillation (AF) complexity is still limited in clinical practice. We propose a noninvasive tool to quantify AF complexity from body surface potential maps (BSPMs) that could be used to choose patients who are eligible for AF ablation and assess therapy impact.Methods: BSPMs (mean duration: 7 ± 4 s) were recorded with a 252-lead vest in 97 persistent AF patients (80 male, 64 ± 11 years, duration 9.6 ± 10.4 months) before undergoing catheter ablation. Baseline cycle length (CL) was measured in the left atrial appendage. The procedural endpoint was AF termination. The ablation strategy impact was defined in terms of number of regions ablated, radiofrequency delivery time to achieve AF termination, and acute outcome. The atrial fibrillatory wave signal extracted from BSPMs was divided in 0.5-s consecutive segments, each projected on a 3D subspace determined through principal component analysis (PCA) in the current frame. We introduced the nondipolar component index (NDI) that quantifies the fraction of energy retained after subtracting an equivalent PCA dipolar approximation of heart electrical activity. AF complexity was assessed by the NDI averaged over the entire recording and compared to ablation strategy.Results: AF terminated in 77 patients (79%), whose baseline AF CL was 177 ± 40 ms, whereas it was 157 ± 26 ms in patients with unsuccessful ablation outcome (p = 0.0586). Mean radiofrequency emission duration was 35 ± 21 min; 4 ± 2 regions were targeted. Long-lasting AF patients (≥12 months) exhibited higher complexity, with higher NDI values (≥12 months: 0.12 ± 0.04 vs. <12 months: 0.09 ± 0.03, p < 0.01) and short CLs (<160 ms: 0.12 ± 0.03 vs. between 160 and 180 ms: 0.10 ± 0.03 vs. >180 ms: 0.09 ± 0.03, p < 0.01). More organized AF as measured by lower NDI was associated with successful ablation outcome (termination: 0.10 ± 0.03 vs. no termination: 0.12 ± 0.04, p < 0.01), shorter procedures (<30 min: 0.09 ± 0.04 vs. ≥30 min: 0.11 ± 0.03, p < 0.001) and fewer ablation targets (<4: 0.09 ± 0.03 vs. ≥4: 0.11 ± 0.04, p < 0.01).Conclusions: AF complexity can be noninvasively quantified by PCA in BSPMs and correlates with ablation outcome and AF pathophysiology

Research of therapeutic alternatives to taxanes for high grade prostate cancers : identification of a gene expression signature predicting response to oxaliplatin

Les cancers de la prostate sont classés en deux catégories. Les cancers de haut grade se distinguent des cancers de bas grade par une plus forte agressivité et un pronostic plus mauvais. Lorsqu’ils deviennent résistants à l’hormonothérapie, les cancers de haut grade sont traités par une chimiothérapie basée sur les taxanes. Néanmoins, les taux de réponse restent faibles. Il existe donc un réel besoin quant à l'identification d'alternatives thérapeutiques qui soient spécifiques de ce type de tumeur. Dans cette optique, notre travail a été de proposer une telle alternative par une approche qui prenne en compte la génétique spécifique des cancers de haut grade. Nous avons exploité une signature de 86 gènes dont le niveau d’expression permet de discriminer entre les tumeurs de haut et de bas grade. Par une approche in silico originale utilisant la banque de données du NCI, nous avons identifié 382 corrélations entre le niveau d’expression de 50 gènes et la sensibilité à 139 agents antiprolifératifs. Parmi ces corrélations, nous avons identifié une signature de 9 gènes qui est spécifique de la réponse à l’oxaliplatine. Cette signature a été confirmée sur le plan fonctionnel dans les lignées cancéreuses prostatiques DU145 et LNCaP. Nous avons donc fourni la preuve de concept que notre approche permet d’identifier de nouvelles molécules pouvant être utilisées en alternative aux taxanes pour traiter spécifiquement les cancers de haut grade. Cette stratégie permet aussi d’identifier de nouveaux marqueurs (gènes) régulant la sensibilité à certains médicaments. Nos résultats démontrent par exemple le rôle des gènes SHMT, impliqués dans la régulation du métabolisme monocarboné, dans la sensibilité spécifique à l’oxaliplatine par un mécanisme qui fait intervenir, du moins en partie, une dérégulation du niveau de méthylation global de l’ADN.Prostate cancers are classified in two categories. High grade cancers are distinguished from low grade cancers by their higher agressivity and worse prognostic. When they become refractory to hormone therapy, high grade cancers are treated with a taxane-based chemotherapy. However, response rates remain low. Therefore, there is a real need for the discovery of new therapeutic alternatives which are specific for this type of tumors. For that purpose, our work aimed at proposing such an alternative with a strategy that took into account the high grade genetic background. We exploited a signature of 86 genes for which expression level could distinguish between low grade and high grade tumours. With an original in silico approach, we searched the NCI databases and identified 382 correlations between 50 genes and the sensitivity to 139 antiproliferative agents. Among these, a signature of 9 genes was able to specifically predict cell response to oxaliplatin. This signature was validated at the functional level in two prostate cancer cell lines, DU145 and LNCaP. We have thus provided the proof-of-concept that our approach allows the identification of new drugs that can be used alternatively to taxanes in order to specifically treat high grade prostate cancers. This strategy also allows the identification of new markers (genes) regulating the sensitivity to various drugs. Our results demonstrate for example the implication of SHMT genes, which are involved in the regulation of the one-carbon metabolism, in the specific sensitivity to oxaliplatin, by a mechanism which involves, at least in part, the deregulation of the global level of DNA methylation

Research of therapeutic alternatives to taxanes for high grade prostate cancers : identification of a gene expression signature predicting response to oxaliplatin

Les cancers de la prostate sont classés en deux catégories. Les cancers de haut grade se distinguent des cancers de bas grade par une plus forte agressivité et un pronostic plus mauvais. Lorsqu’ils deviennent résistants à l’hormonothérapie, les cancers de haut grade sont traités par une chimiothérapie basée sur les taxanes. Néanmoins, les taux de réponse restent faibles. Il existe donc un réel besoin quant à l'identification d'alternatives thérapeutiques qui soient spécifiques de ce type de tumeur. Dans cette optique, notre travail a été de proposer une telle alternative par une approche qui prenne en compte la génétique spécifique des cancers de haut grade. Nous avons exploité une signature de 86 gènes dont le niveau d’expression permet de discriminer entre les tumeurs de haut et de bas grade. Par une approche in silico originale utilisant la banque de données du NCI, nous avons identifié 382 corrélations entre le niveau d’expression de 50 gènes et la sensibilité à 139 agents antiprolifératifs. Parmi ces corrélations, nous avons identifié une signature de 9 gènes qui est spécifique de la réponse à l’oxaliplatine. Cette signature a été confirmée sur le plan fonctionnel dans les lignées cancéreuses prostatiques DU145 et LNCaP. Nous avons donc fourni la preuve de concept que notre approche permet d’identifier de nouvelles molécules pouvant être utilisées en alternative aux taxanes pour traiter spécifiquement les cancers de haut grade. Cette stratégie permet aussi d’identifier de nouveaux marqueurs (gènes) régulant la sensibilité à certains médicaments. Nos résultats démontrent par exemple le rôle des gènes SHMT, impliqués dans la régulation du métabolisme monocarboné, dans la sensibilité spécifique à l’oxaliplatine par un mécanisme qui fait intervenir, du moins en partie, une dérégulation du niveau de méthylation global de l’ADN.Prostate cancers are classified in two categories. High grade cancers are distinguished from low grade cancers by their higher agressivity and worse prognostic. When they become refractory to hormone therapy, high grade cancers are treated with a taxane-based chemotherapy. However, response rates remain low. Therefore, there is a real need for the discovery of new therapeutic alternatives which are specific for this type of tumors. For that purpose, our work aimed at proposing such an alternative with a strategy that took into account the high grade genetic background. We exploited a signature of 86 genes for which expression level could distinguish between low grade and high grade tumours. With an original in silico approach, we searched the NCI databases and identified 382 correlations between 50 genes and the sensitivity to 139 antiproliferative agents. Among these, a signature of 9 genes was able to specifically predict cell response to oxaliplatin. This signature was validated at the functional level in two prostate cancer cell lines, DU145 and LNCaP. We have thus provided the proof-of-concept that our approach allows the identification of new drugs that can be used alternatively to taxanes in order to specifically treat high grade prostate cancers. This strategy also allows the identification of new markers (genes) regulating the sensitivity to various drugs. Our results demonstrate for example the implication of SHMT genes, which are involved in the regulation of the one-carbon metabolism, in the specific sensitivity to oxaliplatin, by a mechanism which involves, at least in part, the deregulation of the global level of DNA methylation

Recherche d'alternatives thérapeutiques aux taxanes dans les cancers de la prostate de hauts grades (identification d'une signature prédictive de la réponse à l'oxaliplatine)

Les cancers de la prostate sont classés en deux catégories. Les cancers de haut grade se distinguent des cancers de bas grade par une plus forte agressivité et un pronostic plus mauvais. Lorsqu ils deviennent résistants à l hormonothérapie, les cancers de haut grade sont traités par une chimiothérapie basée sur les taxanes. Néanmoins, les taux de réponse restent faibles. Il existe donc un réel besoin quant à l'identification d'alternatives thérapeutiques qui soient spécifiques de ce type de tumeur. Dans cette optique, notre travail a été de proposer une telle alternative par une approche qui prenne en compte la génétique spécifique des cancers de haut grade. Nous avons exploité une signature de 86 gènes dont le niveau d expression permet de discriminer entre les tumeurs de haut et de bas grade. Par une approche in silico originale utilisant la banque de données du NCI, nous avons identifié 382 corrélations entre le niveau d expression de 50 gènes et la sensibilité à 139 agents antiprolifératifs. Parmi ces corrélations, nous avons identifié une signature de 9 gènes qui est spécifique de la réponse à l oxaliplatine. Cette signature a été confirmée sur le plan fonctionnel dans les lignées cancéreuses prostatiques DU145 et LNCaP. Nous avons donc fourni la preuve de concept que notre approche permet d identifier de nouvelles molécules pouvant être utilisées en alternative aux taxanes pour traiter spécifiquement les cancers de haut grade. Cette stratégie permet aussi d identifier de nouveaux marqueurs (gènes) régulant la sensibilité à certains médicaments. Nos résultats démontrent par exemple le rôle des gènes SHMT, impliqués dans la régulation du métabolisme monocarboné, dans la sensibilité spécifique à l oxaliplatine par un mécanisme qui fait intervenir, du moins en partie, une dérégulation du niveau de méthylation global de l ADN.Prostate cancers are classified in two categories. High grade cancers are distinguished from low grade cancers by their higher agressivity and worse prognostic. When they become refractory to hormone therapy, high grade cancers are treated with a taxane-based chemotherapy. However, response rates remain low. Therefore, there is a real need for the discovery of new therapeutic alternatives which are specific for this type of tumors. For that purpose, our work aimed at proposing such an alternative with a strategy that took into account the high grade genetic background. We exploited a signature of 86 genes for which expression level could distinguish between low grade and high grade tumours. With an original in silico approach, we searched the NCI databases and identified 382 correlations between 50 genes and the sensitivity to 139 antiproliferative agents. Among these, a signature of 9 genes was able to specifically predict cell response to oxaliplatin. This signature was validated at the functional level in two prostate cancer cell lines, DU145 and LNCaP. We have thus provided the proof-of-concept that our approach allows the identification of new drugs that can be used alternatively to taxanes in order to specifically treat high grade prostate cancers. This strategy also allows the identification of new markers (genes) regulating the sensitivity to various drugs. Our results demonstrate for example the implication of SHMT genes, which are involved in the regulation of the one-carbon metabolism, in the specific sensitivity to oxaliplatin, by a mechanism which involves, at least in part, the deregulation of the global level of DNA methylation.BORDEAUX2-Bib. électronique (335229905) / SudocSudocFranceF

From old alkylating agents to new minor groove binders

International audienc

Recherche de profils de candidats à risque par calcul de regroupement flou relationnel

International audienceThis article proposes to study answer profiles of candidates in the results of the selection contest for student pilots. The aim is to extract risky profiles that match the profiles of candidates who previously failed the practical training. To extract these profiles, data mining tools are used.We also use a new form of fuzzy clustering in order to measure the relevance of such profiles.Cet article propose d'étudier les profils de réponses des candidats aux tests du concours des ´ Elèves Pilotes de Ligne de l'ENAC afin d'extraire les profils à risque qui correspondent à des profils des candidats qui ont précédemment échoué lors de la formation pratique. Pour extraire ces profils, des outils de fouille de données sont utilisés. De plus, on utilise une nouvelle technique de classification floue afin de mesurer la pertinence de tels profils

Gene Expression Signature Predicting High-Grade Prostate Cancer Responses to Oxaliplatin

International audienc

Analysis of Signal-Averaged Electrocardiogram Performance for Body Surface Recordings

International audienc

Non Invasive Assessment of Spatiotemporal Organization of Ventricular Fibrillation through Principal Component Analysis

International audienceIntroduction Ventricular fibrillation (VF) is the main cause of sudden cardiac death. Despite its clinical significance, there is still a lack of quantitative tools to evaluate the degree of myocardial electrical organization during VF. This study puts forward novels markers of VF complexity and stability on body surface potential maps (BSPMs), uantifying the ability of signal features determined through principal component analysis (PCA) to be retrieved along the recording.Methods Biventricular potential mapping was performed through a 252-electrode vest in 27 VF patients (25 male, 49 ± 22 years). BSPMs were divided in 0:5-s segments, each projected on a 3D subspace determined through PCA in the preceding segment. At each time instant, the multilead error E between the input signal and its PCA approximation was expressed in terms of normalized amplitude norm |E| and angle cos(E). Additionally, the nondipolar component index (NDI) was determined as the fraction of energy retained by the first 3 PCA eigenvalues in sliding windows of the same duration. In 24 VF recordings (duration 19.8±6.5 s), average values of the aforementioned indices were computed in 4-second windows at the beginning and at the end of the outputparameter series. Temporal changes in VF complexity were verified through an unpaired Student’s t-test. The same analysis was performed in 5 control recordings in sinus rhythm (SR). Results A significant increase in spatiotemporal complexity was observed during VF, quantified by higher NDI and |E| and lower cos(E) values at the end of the episode (p 0:05).Conclusions This study demonstrates the ability of PCA to capture and quantify changes in signal complexity during VF in a noninvasive framework

Non Invasive Assessment of Spatiotemporal Organization of Ventricular Fibrillation through Principal Component Analysis

Introduction Ventricular fibrillation (VF) is the main cause of sudden cardiac death. Despite its clinical significance, there is still a lack of quantitative tools to evaluate the degree of myocardial electrical organization during VF. This study puts forward novels markers of VF complexity and stability on body surface potential maps (BSPMs), uantifying the ability of signal features determined through principal component analysis (PCA) to be retrieved along the recording.Methods Biventricular potential mapping was performed through a 252-electrode vest in 27 VF patients (25 male, 49 ± 22 years). BSPMs were divided in 0:5-s segments, each projected on a 3D subspace determined through PCA in the preceding segment. At each time instant, the multilead error E between the input signal and its PCA approximation was expressed in terms of normalized amplitude norm |E| and angle cos(E). Additionally, the nondipolar component index (NDI) was determined as the fraction of energy retained by the first 3 PCA eigenvalues in sliding windows of the same duration. In 24 VF recordings (duration 19.8±6.5 s), average values of the aforementioned indices were computed in 4-second windows at the beginning and at the end of the outputparameter series. Temporal changes in VF complexity were verified through an unpaired Student’s t-test. The same analysis was performed in 5 control recordings in sinus rhythm (SR). Results A significant increase in spatiotemporal complexity was observed during VF, quantified by higher NDI and |E| and lower cos(E) values at the end of the episode (p 0:05).Conclusions This study demonstrates the ability of PCA to capture and quantify changes in signal complexity during VF in a noninvasive framework