Institut des Hautes Études du Ministère de l'Intérieur

Abstract Chronic myeloid leukemia (CML) is a chronic disease resulting in myeloid cell expansion through expression of the BCR-ABL1 fusion transcript. Tyrosine kinase inhibitors (TKI) have significantly increased survival of patients with CML, and deep responders may consider stopping the treatment. However, more than 50% of patients relapse and restart TKI, subsequently suffering unknown toxicity. Because CML is a model immune system–sensitive disease, we hypothesize that chimeric antigen receptor (CAR) T cells targeting IL1 receptor-associated protein (IL1RAP) in quiescent CML stem cells may offer an opportunity for a permanent cure. In this study, we produced and molecularly characterized a specific monoclonal anti-IL1RAP antibody from which fragment antigen-binding nucleotide coding sequences were cloned as a single chain into a lentiviral backbone and secured with the suicide gene iCASP9/rimiducid system. Our CAR T-cell therapy exhibited cytotoxicity against both leukemic stem cells and, to a lesser extent, monocytes expressing IL1RAP, with no apparent effect on the hematopoietic system, including CD34+ stem cells. This suggests IL1RAP as a tumor-associated antigen for immunotherapy cell targeting. IL1RAP CAR T cells were activated in the presence of IL1RAP+ cell lines or primary CML cells, resulting in secretion of proinflammatory cytokines and specifically killing in vitro and in a xenograft murine model. Overall, we demonstrate the proof of concept of a CAR T-cell immunotherapy approach in the context of CML that is applicable for young patients and primary TKI-resistant, intolerant, or allograft candidate patients. Significance: These findings present the first characterization and proof of concept of a chimeric antigen receptor directed against IL1RAP expressed by leukemic stem cells in the context of CML.

La documentación histórica proporciona datos que permiten entender los motivos de la desaparición del idioma puquina a la vez que facilita información lingüística que, junto con los estudios arqueológicos, brindan una interpretación de su historia en la época que precede a la conquista inca del Collasuyu, así como de la etapa de su dominio en este territorio. Sobre la base del método de historia regresiva y mediante el empleo de varias disciplinas, como la historia, la arqueología y la lingüística, el presente artículo propone una interpretación de la historia de los últimos puquinahablantes.

Designers' Guides to the Eurocodes series provides comprehensive guidance in the form of design aids, indications for the most convenient design procedures and worked examples for the Eurocodes, with background information to aid the designer in understanding the reasoning behind and the objectives of the codes. Designers' Guide to Eurocode: Basis of Structural Design provides guidance on the interpretation and use of EN 1990 Eurocode: Basis of structural design - the primary document in the Eurocode suite. EN 1990 establishes the principles and requirements for safety, serviceability and durability of structures designed to Eurocodes and should be applied whenever Eurocodes 1 to 9 (EN 1991 to EN 1999) are used for the structural design or appraisal of buildings and other civil engineering works. The lead title in the series, this guide provides explanation and commentary to the clauses in EN 1990, including the relationship to the other Eurocodes and information on the implementation of the Eurocodes and their use, with regard to National Annexes. Worked examples emphasise the rules that differ from those in previous codes. This second edition has been fully updated and revised to cover the UK National Annex to BS EN 1990 and PSI(?) factors for execution (buildings) and includes additional examples and references to secondary guidance. This guide is essential reading for: in fact, everyone who will be affected by the Eurocodes.

<h3>Abstract</h3> The American Society of Regional Anesthesia and Pain Medicine9s Third Practice Advisory on local anesthetic systemic toxicity is an interim update from its 2010 advisory. The advisory focuses on new information regarding the mechanisms of lipid resuscitation, updated frequency estimates, the preventative role of ultrasound guidance, changes to case presentation patterns, and limited information related to local infiltration anesthesia and liposomal bupivacaine. In addition to emerging information, the advisory updates recommendations pertaining to prevention, recognition, and treatment of local anesthetic systemic toxicity. <h3>What's New in This Update?</h3> This interim update summarizes recent scientific findings that have enhanced our understanding of the mechanisms that lead to lipid emulsion reversal of LAST, including rapid partitioning, direct inotropy, and post-conditioning. Since the previous practice advisory, epidemiological data have emerged that suggest a lower frequency of LAST as reported by single institutions and some registries, nevertheless a considerable number of events still occur within the general community. Contemporary case reports suggest a trend toward delayed presentation, which may mirror the increased use of ultrasound guidance (fewer intravascular injections), local infiltration techniques (slower systemic uptake), and continuous local anesthetic infusions. Small patient size and sarcopenia are additional factors that increase potential risk for LAST. An increasing number of reported events occur outside of the traditional hospital setting and involve non-anesthesiologists.

This article presents a sociological and historical analysis of female imprisonment in Peru. The authors show how, from the beginning of the republican era until the twenty-first century, patriarchal cultural models implicating sexual, racial, and social dimensions frame the domestication of female bodies. The article also demonstrates the transnationalization of criminality and mass prison building that characterize the dynamics of women’s imprisonment in Peru. These trends are linked with the growth of neoliberalism, which has significant consequences for the global growth of female marginalization. Such phenomena, which undoubtedly shape women’s criminality worldwide, are reflected in the Peruvian female prison population.

BACKGROUND: Intrapartum single-dose nevirapine plus third trimester maternal and infant zidovudine are essential components of programs to prevent mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings. The persistence of nevirapine in the plasma for 3 weeks postpartum risks selection of resistance mutations to nonnucleoside reverse-transcriptase inhibitors (NNRTIs). We hypothesized that a 1-month zidovudine-didanosine course initiated at the same time as single-dose nevirapine (sdNVP) would prevent the selection of nevirapine-resistance mutations. METHODS: HIV-infected pregnant women in the PHPT-4 cohort with CD4 cell counts >250 cells/mm3 received antepartum zidovudine from the third trimester until delivery, sdNVP during labor, and a 1-month zidovudine-didanosine course after delivery. These women were matched on the basis of baseline HIV load, CD4 cell count, and duration of antepartum zidovudine to women who received sdNVP in the PHPT-2 trial (control subjects). Consensus sequencing and the more sensitive oligonucleotide ligation assay were performed on samples obtained on postpartum days 7-10, 37-45, and 120 (if the HIV load was >500 copies/mL) to detect K103N/Y181C/G190A mutations. RESULTS: The 222 PHPT-4 subjects did not differ from matched control subjects in baseline characteristics except for age. The combined group median CD4 cell count was 421 cells/mm3 (interquartile range [IQR], 322-549 cells/mm3), the median HIV load was 3.45 log10 copies/mL (IQR, 2.79-4.00 log10 copies/mL), and the median duration of zidovudine prophylaxis was 10.4 weeks (IQR, 9.1-11.4 weeks). Using consensus sequencing, major NNRTI resistance mutations were detected after delivery in 0% of PHPT-4 subjects and 10.4% of PHPT-2 controls. The oligonucleotide ligation assay detected resistance in 1.8% of PHPT-4 subjects and 18.9% of controls. Major NNRTI resistance mutations were detected by either method in 1.8% of PHPT-4 subjects and 20.7% of controls (P < .001). CONCLUSIONS: A 1-month postpartum course of zidovudine plus didanosine prevented the selection of the vast majority of NNRTI resistance mutations.

No decorrer do século XX, o Brasil desenvolveu uma diplomacia cultural original a fim de defender seus interesses econômicos e estratégicos no mundo. A partir dos anos 1920, o Itamaraty defendeu uma política cultural pragmática, cujos conteúdos e estruturas sofreram importantes modificações conforme o período, o regime político, a composição do corpo diplomático e as diferentes concepções de sua identidade nacional. O artigo analisa a gênese da diplomacia cultural brasileira através de suas instituições, meios de atuação, objetivos e países destinatários, e estuda a significação histórica da ação cultural para uma potência emergente do hemisfério ocidental.

Implicit attitude automatically influences our judgments without our being aware of it. This article aims to introduce the concept of implicit attitude and its main measurement tool, the Implicit Association Test, and their significance in the study of consumer behavior.

Les responsables musulmans font l’objet, en France, d’une approche normative (quelle est la nature de l’influence qu’ils exercent ?), recouvrant des enjeux intégrationnistes et sécuritaires qui ont trouvé une nouvelle actualité avec les débats sur la radicalisation. Dans la mesure où la capacité des responsables musulmans à incarner un islam socialement acceptable (l’« islam de France ») en public tend à devenir une ressource de légitimation de l’autorité religieuse, ceux-ci s’impliquent dans l’élaboration de l’islam civil que l’État et la société recherchent depuis les années 1980/1990.

A discussion on the relation between law and literature in coordinating conjunction, the 'AND' between the two is presented. The author opines that law and literature complement each other so well because, although they rely on different means of expression, they are both facets of a shared cultural wealth.

Cross-national comparisons of crime across the world consistently show that homicide rates are higher in more impoverished countries. However, the role of formal social controls as mediators between social conditions and homicide has never been investigated across a large number of countries. To provide data on the efficiency of criminal justice systems across the world, we found 1,223 experts and had them fill out a questionnaire, providing data for 145 countries. Results from structural equations models (Amos) show that adverse social conditions (collective and individual poverty, inequality, and youthfulness of the population) downwardly affect the level of formal social control (application of the rule of law, low corruption rate, effectiveness of the criminal justice system, and satisfaction with the criminal justice agencies). Low levels of formal social control lead to higher levels of homicide. In other words, the effect of adverse social conditions on homicide is mediated by formal social control.

Résumé Le marché français du cannabis connaît des changements propres à un marché arrivé désormais à maturité et peut être en conséquence qualifié de marché du THC. L’entrée de nouveaux concurrents, la diversification des produits, les variations de prix et l’augmentation de la qualité en sont les principales évidences ; ajoutons à cela la modification sociologique des structures d’offre. Ce document discute des implications que ces changements peuvent avoir sur le système traditionnel d’offre et sur les moyens mis en œuvre dans la lutte contre les stupéfiants.

La réflexion de l’auteur prend racine dans la question suivante : la démocratie moderne, qui cantonne le droit à régler uniquement les relations entre les individus et lui interdit de se prononcer sur la vie bonne, condamne-t-elle nos sociétés à n’être qu’une agrégation d’« hommes-seuls-au-monde » jouissant d’une liberté dont l’usage ne regarde qu’eux ? Dans son texte, il tente de démontrer comment l’apparition dans le droit contemporain du principe de la dignité humaine vient contrecarrer la montée en puissance de l’individu-roi.

BACKGROUND: On tropical regions, phosphorus (P) fixation onto aluminum and iron oxides in soil clays restricts P diffusion from the soil to the root surface, limiting crop yields. While increased root surface area favors P uptake under low-P availability, the relationship between the three-dimensional arrangement of the root system and P efficiency remains elusive. Here, we simultaneously assessed allelic effects of loci associated with a variety of root and P efficiency traits, in addition to grain yield under low-P availability, using multi-trait genome-wide association. We also set out to establish the relationship between root architectural traits assessed in hydroponics and in a low-P soil. Our goal was to better understand the influence of root morphology and architecture in sorghum performance under low-P availability. RESULT: In general, the same alleles of associated SNPs increased root and P efficiency traits including grain yield in a low-P soil. We found that sorghum P efficiency relies on pleiotropic loci affecting root traits, which enhance grain yield under low-P availability. Root systems with enhanced surface area stemming from lateral root proliferation mostly up to 40 cm soil depth are important for sorghum adaptation to low-P soils, indicating that differences in root morphology leading to enhanced P uptake occur exactly in the soil layer where P is found at the highest concentration. CONCLUSION: Integrated QTLs detected in different mapping populations now provide a comprehensive molecular genetic framework for P efficiency studies in sorghum. This indicated extensive conservation of P efficiency QTL across populations and emphasized the terminal portion of chromosome 3 as an important region for P efficiency in sorghum. Increases in root surface area via enhancement of lateral root development is a relevant trait for sorghum low-P soil adaptation, impacting the overall architecture of the sorghum root system. In turn, particularly concerning the critical trait for water and nutrient uptake, root surface area, root system development in deeper soil layers does not occur at the expense of shallow rooting, which may be a key reason leading to the distinctive sorghum adaptation to tropical soils with multiple abiotic stresses including low P availability and drought.

The Italian judiciary has been under the spotlight for more than two decades. The key criticism addressed to it has been the lack of organizational capacity, which is reflected in the trial time frame. After 2000, European institutions launched a new and comprehensive policy stream, targeting the administrative and organizational capacities of courts and public prosecutor offices. The pivotal policy instrument is represented by standards and soft law in general. By referring to four case studies, analysed in depth on the basis of a qualitative approach, this work engages in a critical appraisal of the New Public Management-inspired judicial policies and the way in which they have been implemented in the judicial sector in Italy. Points for practitioners This article makes a point about the structural and institutional conditions that turn out as pivotal factors to ensure an effective and efficient governance by standards. In other terms, the argument deployed herein concerns the function of a regulative agency, which might have the shape and the format of a ministerial unit, where the uniformity and the equality of the services delivered by a public institution or a network of public institutions are the outcome of the implementation of legally binding and non-legally binding norms. This is a key point, then, for public officers serving not only in the judicial sector.

Abstract Seed health is an indispensable prerequisite of food security. While the toolkit of plant protection products is currently limited, evidence suggests that the seed microbiome could protect seeds from pathogens. Thus, given their possible disease suppressive potential, we tested 11 different pathosystems to achieve the following proof-of-concept: seed microbiomes can be beneficial for seed health through conferring disease suppression. This study focused on beetroot, onion, spinach, pepper, coriander, red fescue and perennial ryegrass seeds, with each crop being challenged with one or two from a total of six pathogens, namely Pythium ultimum (or a Pythium sp.), Setophoma terrestris , Fusarium oxysporum , Phytophthora capsici , Laetisaria fuciformis and a mix of Puccinia sp. isolates. Each seed lot of each crop was tested with and without treatment with a disinfectant as a proxy for comparing intact seed microbiomes with seed microbiomes after partial elimination by disinfection. We found disease suppression in two pathosystems. Beetroot and spinach seed lots were able to suppress disease caused by P. ultimum when their microbiomes were intact but not after seed disinfection. We speculate that this relates to the microorganisms residing on and in the seed. Yet, seed microbiome disease suppression was not found in all pathosystems, highlighting the variation in seed morphology, plant cultivars, pathogens and seed disinfection treatments. A holistic understanding of the characteristics of seeds that harbour suppressive microbiomes as well as the pathogens that are sensitive to suppression could lead to more targeted and informed seed processing and treatment and, consequently, to the sustainable management of seedling diseases.

Au début du XXIe siècle, le catholicisme latino-américain est confronté à une crise multiforme qui semble mettre en jeu son avenir. Loin de prendre la forme d’une sécularisation ou d’un affaiblissement de la religiosité populaire, celle-ci se traduit principalement par le transfert de fidèles vers d’autres affiliations confessionnelles et constitue une véritable rupture historique après quatre siècles et demi de monopole catholique. À partir d’un rappel historique de la place du catholicisme dans les sociétés latino-américaines depuis la Conquête, cet article met en lumière les contradictions qui pèsent aujourd’hui sur les stratégies de reconquête déployées par l’Église catholique, ainsi que le décalage croissant entre les prescriptions doctrinales et l’aspiration à la modernisation des sociétés latino-américaines.

Pero los indígenas nos hemos despertado poquito. Ahora sabemos que los terratenientes y oligarcas crearon las leyes, las escrituras y las administraciones y policías para hacer de nosotros esclavos y tenernos bajo el yugo y la ignorancia. Todo esto porque no les conviene que seamos libres. Sabemos también que tenemos derecho a la tierra: porque nosotros fuimos los primeros que nacimos en estas tierras, no los blancos terratenientes; y porque trabajamos siempre desde los antepasados...Un miemb...

Cet article s’intéresse à la conception du droit à l’œuvre dans les travaux de S. Silbey et observe que celle-ci la conduit à refuser de rouvrir la question des « sources sociales » du droit. Or, à partir de quel stade les pratiques observées relèvent plus d’une forme de « droit vivant » agissant au niveau d’un groupe social que de la reproduction du droit de l’État ? Indépendamment même de la question des critères de la « juridicité », peut-on se permettre d’évacuer le problème de savoir quand, précisément, est-ce que l’on bascule d’un côté ou de l’autre ? On peut penser que c’est le dispositif d’enquête lui-même – l’absence d’approche ethnographique – qui empêche S. Silbey de saisir la réciprocité des interrelations entre pratiques sociales et droit formel, et donc de dépasser la seule question de l’expérience quotidienne de ce dernier.

ABSTRACT: Inflammatory form of Waldenström macroglobulinemia (iWM) predicts outcomes after immuno-chemotherapy and Bruton tyrosine kinase inhibitors, but its origin is unknown. Here, we unravel increased clonal hematopoiesis in patients with iWM (61% vs 23% in noninflammatory WM), suggesting a contribution of environmental cells to iWM.