JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition

Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617Fand mutant IDH1R132Hor Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617FIdh2R140Q–mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mutand IDH2mutmutations. Taken together, these data suggest that combined JAK and IDH inhibition May offer a therapeutic advantage in this high-risk MPN subtype.Damon Runyon Cancer Research Foundation (DRG-2241-15)Howard Hughes Medical Institute (Faculty Scholars Award)Stand Up To CancerNational Cancer Institute (U.S.) (P50CA165962)National Cancer Institute (U.S.) (P30CA14051)Koch Institute for Integrative Cancer Research ( Dana-Farber Harvard Cancer Center Bridge Project)Leukemia & Lymphoma Society of America. Specialized Center of Research (SCOR) ProgramNational Institutes of Health (U.S.) (grant U54OD020355-01)National Institutes of Health (U.S.) (grant NCI R01CA172636)National Institutes of Health (U.S.) (grant R35CA197594)National Cancer Institute (U.S.) (Cancer Center Support Grant (P30 CA008747)

Vitamin D-Related Genes, Blood Vitamin D Levels and Colorectal Cancer Risk in Western European Populations

Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini-Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor beta (TGF beta) signaling was associated with CRC risk (P <= 0.001), with most statistically significant genes being SMAD7 (P-BH = 0.008) and SMAD3 (P-BH = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (P = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction P = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Period Control of the Coupled Clock and Cell Cycle Systems

International audienceThe mammalian clock and cell cycle are two essential biological oscillators. In this work we investigate the coupling of these os-cillators via non-linear dynamical modeling. We use previously developed reduced models of these systems and study a molecular interaction of MPF (mitosis promoting factor) repression by the CLOCK:BMAL1 protein complex, via induction of the repressor wee1. Furthermore, we propose an hypothesis whereby the clock responds to cell cycle Growth Factors (GFs) via a pathway involving the non-essential cell cycle complex cyclin D/cdk4 and study this interaction in the context of unidirectional clock → cell cycle coupling. We observe 1:1, 3:2, 4:3, 5:4 ratios of clock to cell cycle period and identify GF and the coupling strength c b as decisive control parameters for the system's state of synchronization. Synchronization ratios differing from 1:1, namely 3:2 and 5:4, have been observed in cells treated with the corticosteroid Dexamethasone (Dex). Here, we study Dex application and are able to reproduce the induction of ratios differing from 1:1. Finally, because slowing down the cell cycle is very relevant in the context of cancer therapies, we devise particular protocols of cell cycle period control with the use of clock inputs that are successful in substantially slowing down the cell cycle by the use of the system's synchronization dynamics, obtaining 2:3, 3:4, 4:5 ratios of clock to cell cycle period

Qui veut laver ma blouse ? La légitimation collective d’activités teintes. Le cas des équipes de gestion de pôles

National audienceFrench hospitals’ governance reform has, directly or not, created new roles: clinical directors, senior nurse assistants, business managers and executive managers. These roles are still recent and not yet legitimate within hospitals. Furthermore, they are associated with a strong social stigma in those organizations: care management. Our work aims at better understanding the way clinical directions’ teams consider their management activities as dirty work; and the strategies through which they try to legitimate these activities in front of their colleagues. We carried out a case study of 7 “Mother-Child” clinical directions’ teams in France, through a qualitative methodology (56 interviews, including 25 interviews with targeted actors; 20 observations of directorate meetings). Our results show that activity legitimization strategies vary depending on actors and teams. They are both organizationally based (delegation) and discursively based (reframing, recalibrating, audience diversifying). We specifically suggest that these strategies depend on clinical directions’ team organization. We discuss two layouts of strategies: strategies of clinical director’s delegation and those of collective commitment. Tinted roles’ legitimization thus depends on both individuals’ discursive resources (and places for discussions) and individual’s power within the organization (and hierarchical and functional relationships).Directement ou non, la nouvelle gouvernance hospitalière a créé de nouveaux rôles : chef de pôle d’activité, cadre coordonnateur de pôle, cadre administratif de pôle, directeur délégué de pôle. Ces rôles, encore récents et peu légitimes au sein des hôpitaux, sont en plus associés à une teinte sociale encore prégnante dans ces organisations : la gestion des soins. Notre travail vise à mieux comprendre la manière dont les équipes de pôle conçoivent leurs activités de gestion en tant que sale boulot ; ainsi que les stratégies par lesquelles ils tentent de les légitimer auprès de leurs collègues. Pour cela, nous avons mené une étude de 7 cas d’équipes de gestion de pôles « Mère-Enfant » en France, à partir d’une démarche qualitative (56 entretiens, dont 25 avec les acteurs ciblés ; 20 observations de réunions de pôle). Nos résultats montrent que les stratégies de légitimation des activités diffèrent selon les acteurs et les équipes de pôle. Elles sont à la fois d’ordre organisationnel (délégation) et discursif (recadrage, recalibrage, diversification de l’audience). En particulier, nous avançons que ces stratégies découlent des modes d’organisation dans chaque équipe de pôle. Notre discussion nous amène à distinguer deux configurations de stratégies : les stratégies par délégation du chef de pôle et celles par endossement de l’ensemble de l’équipe. La légitimation de rôles teintés dépend donc à la fois des ressources discursives des individus (et donc des instances de dialogue) mais aussi du pouvoir de chacun dans l’organisation (et donc des liens hiérarchiques et fonctionnels qui les unissent)

Certifié « Cadre administratif de pôle ». L’encastrement identitaire pour légitimer un nouveau rôle

International audienceThe hospital new governance reform has created a brand new role of administrative man- ager of clinical directorates. This administrative manager should assist a clinical director, along with a senior nurse, however he has no clear instruction about his/her activities, while his/her environment is highly institutionalized. This article aims at investigating the legitimization process of this new role within clinical directorates’ teams: how adminis- trative managers try to legitimize their role as perceived by their colleagues? To address the issue, we resort to the literature relating to both new organizational practices legit- imization, and identity work; our empirics consists in case studies of 4 “Mother-Child” clinical directorate teams in France, each of one involving an administrative manager. We proceed through qualitative methods including 30 interviews and 8 meeting observations. Our results show how administrative managers struggle to integrate their identity into their colleagues’ work systems, while justifying to them the usefulness of their role. We finally discuss the concept of identity embeddedness in relation to neo-institutional and identity work theories, as well as implications for clinical directory teams.La nouvelle gouvernance hospitalière a créé un nouveau rôle de cadre administratif de pôle d’activité, rôle totalement inédit dans les hôpitaux. Censé assister le chef de pôle, en collaboration avec un cadre coordonnateur, ce cadre administratif n’a cependant pas une ligne de fonctionnement claire, d’autant plus dans un environnement qui, lui, est fortement institutionnalisé. Nous posons dans ce travail la question de la légitimation de ce nouveau rôle au sein des équipes de pôle : comment les cadres administratifs procèdent-ils pour légitimer leur rôle aux yeux de leurs collègues ? Pour y répondre, nous mobilisons la litté- rature concernant la légitimation de nouvelles pratiques ainsi que celle relative au travail identitaire ; puis nous utilisons une étude de 4 cas d’équipes de pôle « Mère-Enfant » en France, comprenant chacune un cadre administratif, à partir d’une démarche qualitative (30 entretiens, 8 observations de réunions). Nos résultats montrent comment les cadres administratifs de pôle s’attèlent à insérer leur identité dans le fonctionnement des équipes de pôle, tout en justifiant l’utilité de leur rôle auprès de ces acteurs. Nous discutons finalement le concept d’encastrement identitaire en lien avec la théorie néo-institutionnelle et celle du travail identitaire, ainsi que les implications pour la gestion des équipes de pôle

Rapport de stage de DEA Informatique Sujet : Etablissement d&apos;un système transactionnel relationnel/objet pour longues transactions.

The concurrency control problem has been for a long time a source of research in the database community. If traditional databases use models that have been validated, they don&apos;t fully answer to specific situations as the problem of long transactions met in software development environments (SDEs) and CAD/CAM systems. This paper presents a solution that can solve this problem of long transactions and offers the possibility of using independently a relational or an object representation of data. Such a system provides a cooperative support for advanced database applications and can allow a network query to be more efficient. 1. Introduction Traditional solutions that prevent databases from corruption or incompatible access due to the share of information between users are not suited with advanced database applications as software development environments or CAD/CAM systems that make transactions can last several hours or days, as the result of human interaction. Thus, a new solution for ..

Fast stabbing of boxes in high dimensions

Theme 2 - Genie logiciel et calcul symbolique. Projet PrismeSIGLEAvailable at INIST (FR), Document Supply Service, under shelf-number : 14802 E, issue : a.1996 n.2854 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc