Bioinformatics for precision medicine in oncology: principles and application to the SHIVA clinical trial

Precision medicine (PM) requires the delivery of individually adapted medical care based on the genetic characteristics of each patient and his/her tumor. The last decade witnessed the development of high-throughput technologies such as microarrays and next-generation sequencing which paved the way to PM in the field of oncology. While the cost of these technologies decreases, we are facing an exponential increase in the amount of data produced. Our ability to use this information in daily practice relies strongly on the availability of an efficient bioinformatics system that assists in the translation of knowledge from the bench towards molecular targeting and diagnosis. Clinical trials and routine diagnoses constitute different approaches, both requiring a strong bioinformatics environment capable of (i) warranting the integration and the traceability of data, (ii) ensuring the correct processing and analyses of genomic data, and (iii) applying well-defined and reproducible procedures for workflow management and decision-making. To address the issues, a seamless information system was developed at Institut Curie which facilitates the data integration and tracks in real-time the processing of individual samples. Moreover, computational pipelines were developed to identify reliably genomic alterations and mutations from the molecular profiles of each patient. After a rigorous quality control, a meaningful report is delivered to the clinicians and biologists for the therapeutic decision. The complete bioinformatics environment and the key points of its implementation are presented in the context of the SHIVA clinical trial, a multicentric randomized phase II trial comparing targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer. The numerous challenges faced in practice during the setting up and the conduct of this trial are discussed as an illustration of PM application

Impact of new European grid codes requirements on anti-islanding protection, a case study

International audienc

Connaissances, attitudes et pratiques des adolescents de la ville de Brazzaville en matiere de la prevention du COVID-19 : Knowledge, attitudes and practices of adolescents in the city of Brazzaville with regard to the prevention of COVID-19

Contexte : Les nombres de cas confirmés de COVID-19 et de décès dus à cette pandémie ne cessent d’augmenter. En République du Congo, Brazzaville est le plus grand foyer de contamination. L’objectif de cette étude est de déterminer les connaissances, attitudes et pratiques de la population jeune face à cette épidémie de COVID-19. Méthode : Une étude transversale, descriptive et analytique a été menée auprès de 323 adolescents de 14-18 ans. Les données ont été recueillies par un questionnaire en ligne. Résultats : Parmi les 323 participants à l’étude, plus de la moitié déclaraient avoir reçu des informations sur le COVID-19. La majorité des participants avaient répondu que les principaux symptômes de la COVID-19 étaient la fièvre, la toux sèche, le mal de gorge, la fatigue, les difficultés respiratoires, et le nez qui coule. Les modes de transmission de la COVID-19 étaient connus : le contact direct avec une personne atteinte, les gouttelettes respiratoires d’un sujet infecté et les objets contaminés. Quant aux attitudes et pratiques, la plupart des participants se lavaient les mains régulièrement au savon. Peu d’entre eux respectaient la distanciation sociale d’au moins 1 m dans les milieux publics, toussaient dans le creux du coude et dans un mouchoir jetable. Les sujets portaient régulièrement les masques de protection artisanaux. Conclusion : Brazzaville est le plus grand foyer de contamination en République du Congo. Les résidents adolescents adoptent des attitudes et pratiques parfois défavorables malgré leur niveau bon de connaissance sur la COVID-19. Une intervention à l’éduction pour la santé plus efficace à cette population parait nécessaire et urgente afin de réduire le risque de contamination cette pandémie. Background: The number of confirmed cases and deaths due to this pandemic continues to increase. In the Republic of Congo, Brazzaville is the largest source of contamination. The objective of this study is to determine the knowledge, attitudes and practices of the youth population with regard to this COVID-19 epidemic. Method: A cross-sectional, descriptive and analytical study was conducted with 323 adolescents aged 14-18 years. Data were collected through an online questionnaire. Results: Of the 323 participants in the study, more than half reported receiving information about COVID-19. The majority of participants responded that the main symptoms of COVID-19 were fever, dry cough, sore throat, fatigue, difficulty breathing, and runny nose. The modes of transmission of COVID-19 were known direct contact with an infected person, respiratory droplets from an infected subject and contaminated objects. In terms of attitudes and practices, most participants washed their hands regularly with soap. Few of them respected the social distance of at least 1 m in public places, coughed in the crook of the elbow and in a disposable handkerchief. Subjects regularly wore the homemade protective masks. Conclusion: Brazzaville is the largest outbreak in the Republic of Congo. Adolescent residents sometimes adopt unfavourable attitudes and practices despite their good level of knowledge about VIDOC-19. A more effective health education intervention for this population seems necessary and urgent to reduce the risk of contamination of this pandemic

Stability of the threshold voltage in fluorine-implanted normally-off AlN/GaN HEMTs co-integrated with commercial normally-on GaN HEMT technology

International audienceFluorine ion migration in normally-off AlN/GaN HEMTs fabricated by fluorine ion plasma implantation technology is evidenced. Devices under test are co-integrated into the OMMIC commercial D006GH/D01GH MMIC process, providing fluorine-free normally-on HEMTs. Gate reverse bias step-stress experiment at a drain fixed voltage of 0 V, carried out as well on normally-on ones as on normally-off ones, shows a permanent negative shift in the threshold voltage V-th of normally-off devices only. V-th degradation is starting at a V-GS,V- stress of -8 V, with a negative shift from 0 V to -0.4 V at V-GS,V-stress = -30 V, while the transconductance g(m) and g(m,max) remains unchanged prior to breakdown that occurred at V-GS,V-stress ranging between -26 and -32 V. Since the positive threshold voltage of these devices is induced by F-ions dose and position, the above result suggests a possible drift of F-ions away from the 2DEG channel. A field-assisted migration mechanism of fluorine ions is proposed and supported by the absence of V-th degradation in fluorine-free normally-on devices

Study of Turnip mosaic virus transmission activation by aphids

Study of Turnip mosaic virus transmission activation by aphids. 17. Rencontres de Virologie Végétale (RVV 2019

Turnip mosaic virus is a second example of a virus using transmission activation for plant-to-plant propagation by aphids

BGPI : équipe 2International audienceCauliflower mosaic virus (CaMV; family Caulimoviridae) responds to the presence of aphid vectors on infected plants by forming specific transmission morphs. This phenomenon, coined transmission activation (TA), controls plant-to-plant propagation of CaMV. A fundamental question is whether other viruses rely on TA. Here, we demonstrate that transmission of the unrelated turnip mosaic virus (TuMV; family Potyviridae) is activated by the reactive oxygen species H2O2 and inhibited by the calcium channel blocker LaCl3 H2O2-triggered TA manifested itself by the induction of intermolecular cysteine bonds between viral helper component protease (HC-Pro) molecules and by the formation of viral transmission complexes, composed of TuMV particles and HC-Pro that mediates vector binding. Consistently, LaCl3 inhibited intermolecular HC-Pro cysteine bonds and HC-Pro interaction with viral particles. These results show that TuMV is a second virus using TA for transmission but using an entirely different mechanism than CaMV. We propose that TuMV TA requires reactive oxygen species (ROS) and calcium signaling and that it is operated by a redox switch.IMPORTANCE Transmission activation, i.e., a viral response to the presence of vectors on infected hosts that regulates virus acquisition and thus transmission, is an only recently described phenomenon. It implies that viruses contribute actively to their transmission, something that has been shown before for many other pathogens but not for viruses. However, transmission activation has been described so far for only one virus, and it was unknown whether other viruses also rely on transmission activation. Here we present evidence that a second virus uses transmission activation, suggesting that it is a general transmission strategy

The Standard Output : A Tool-Agnostic Modeling Storage Format

New standards have been recently defined and implemented enabling a reliable exchange of pharmacometric models across software tools, and facilitating collaborative drug and disease modeling and simulation (M&S) activities. Among these, the Standard Output (SO) has been proposed as the tool‐independent exchange and storage format for typical M&S results. The SO integration within the Drug Disease Model Resource (DDMoRe) interoperability framework (IOF) has already shown its potential for enabling effective data flow across modeling tasks and facilitating information retrieval

The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effects

International audienceSmall airway remodeling (SAR) is a key phenomenon of airflow obstruction in smokers, leading to chronic obstructive pulmonary disease (COPD). SAR results in an increased thickness of small airway walls, with a combination of peribronchiolar fibrosis with increased fibrous tissue and accumulation of mesenchymal and epithelial cells. SAR pathogenesis is still unclear but recent data suggest that alterations in telomerase activity could represent a possible underlying mechanism of SAR. Our study was dedicated to identify a potential protective role of TA-65, a pharmacological telomerase activator, in a cigarette smoke (CS) model of SAR in mice, and to further precise if extra-telomeric effects of telomerase, involving oxidative stress modulation, could explain it. C57BL/6J mice were daily exposed to air or CS during 4 weeks with or without a concomitant administration of TA-65 starting 7 days before CS exposure. Morphological analyses were performed, and mucus production, myofibroblast differentiation, collagen deposition, as well as transforming growth factor-β1 (TGF-β1) expression in the small airway walls were examined. In addition, the effects of TA-65 treatment on TGF-β expression, fibroblast-to-myofibroblast differentiation, reactive oxygen species (ROS) production and catalase expression and activity were evaluated in primary cultures of pulmonary fibroblasts and/or mouse embryonic fibroblasts in vitro. Exposure to CS during 4 weeks induced SAR in mice, characterized by small airway walls thickening and peribronchiolar fibrosis (increased deposition of collagen, expression of α-SMA in small airway walls), without mucus overproduction. Treatment of mice with TA-65 protected them from CS-induced SAR. This effect was associated with the prevention of CS-induced TGF-β expression in vivo, the blockade of TGF-β-induced myofibroblast differentiation, and the reduction of TGF-β-induced ROS production that correlates with an increase of catalase expression and activity. Our findings demonstrate that telomerase is a critical player of SAR, probably through extra-telomeric anti-oxidant effects, and therefore provide new insights in the understanding and treatment of COPD pathogenesis

The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effects

Abstract Small airway remodeling (SAR) is a key phenomenon of airflow obstruction in smokers, leading to chronic obstructive pulmonary disease (COPD). SAR results in an increased thickness of small airway walls, with a combination of peribronchiolar fibrosis with increased fibrous tissue and accumulation of mesenchymal and epithelial cells. SAR pathogenesis is still unclear but recent data suggest that alterations in telomerase activity could represent a possible underlying mechanism of SAR. Our study was dedicated to identify a potential protective role of TA-65, a pharmacological telomerase activator, in a cigarette smoke (CS) model of SAR in mice, and to further precise if extra-telomeric effects of telomerase, involving oxidative stress modulation, could explain it. C57BL/6J mice were daily exposed to air or CS during 4 weeks with or without a concomitant administration of TA-65 starting 7 days before CS exposure. Morphological analyses were performed, and mucus production, myofibroblast differentiation, collagen deposition, as well as transforming growth factor-β1 (TGF-β1) expression in the small airway walls were examined. In addition, the effects of TA-65 treatment on TGF-β expression, fibroblast-to-myofibroblast differentiation, reactive oxygen species (ROS) production and catalase expression and activity were evaluated in primary cultures of pulmonary fibroblasts and/or mouse embryonic fibroblasts in vitro. Exposure to CS during 4 weeks induced SAR in mice, characterized by small airway walls thickening and peribronchiolar fibrosis (increased deposition of collagen, expression of α-SMA in small airway walls), without mucus overproduction. Treatment of mice with TA-65 protected them from CS-induced SAR. This effect was associated with the prevention of CS-induced TGF-β expression in vivo, the blockade of TGF-β-induced myofibroblast differentiation, and the reduction of TGF-β-induced ROS production that correlates with an increase of catalase expression and activity. Our findings demonstrate that telomerase is a critical player of SAR, probably through extra-telomeric anti-oxidant effects, and therefore provide new insights in the understanding and treatment of COPD pathogenesis