Fra Angelico : perspectives de recherche, passées et futures

Cet essai dresse un bilan des études récentes sur Fra Angelico, à travers l’analyse de la remarquable floraison de publications et d’expositions consacrées à l’artiste dominicain, en Italie et ailleurs. La peinture de Fra Angelico, figure charnière de la transition entre le Moyen Âge et la Renaissance, théologien thomiste mais aussi interprète précoce de l’humanisme albertien, offre en effet un terrain fécond à une multiplicité de recherches : recherches iconologiques et exégétiques, par exemple sur la structure scripturale et figurative complexe de l’Armoire des ex-voto d’argent ; recherches sur les sources visuelles de sa synthèse entre la préciosité du gothique tardif, les nouveautés de la Renaissance et l’émulation programmatique du modèle défini par Giotto ; recherches sur ses caractéristiques stylistiques, afin de mettre à jour son catalogue et sa chronologie (comme lors des expositions organisées en 2005 à New York et en 2009 à Rome), en s’appuyant aussi sur des technologies diagnostiques telles que la réflectographie aux rayons infrarouges (par exemple à l’occasion de restaurations, dont la dernière en date est celle du Tabernacle des Tisseurs de lin) ; recherches sur sa production de dessins et d’enluminures ; recherches sur les ressources fournies par les archives et les documents qui éclairent son activité, tant à Florence qu’à Rome. Il est souhaitable, pour l’avenir, que ces investigations échappent à l’hyperspécialisation, et qu’elles se montrent capables de rassembler les éléments historiques, formels et iconographiques, en une vision très informée, bien en accord avec la « densité » de la peinture de Fra Angelico.Through an analysis of the countless publications and exhibitions, both in Italy and elsewhere, dedicated to the Fra Angelico, this essay offers a survey of recent studies on the Dominican artist. The art of Fra Angelo, who was a pivotal figure in the shift from medieval to Renaissance, a Thomistic theologian who was at the same time an early interpreter of Albertian humanism, offers fertile ground for a plethora of research topics : questions of iconology and exegesis, related, for example to the complex scriptural and figurative structure of the Armadio degli Argenti ; studies on the visual sources of the artist’s synthesis of late-gothic refinement, the innovations of the Renaissance and emulation of the Giottesque model ; enquiries into his stylistic characteristics in order to update his catalogue of works and their chronology (as during the exhibitions in New York in 2005 and Rome in 2009), including the use of diagnostic technology such as infrared reflectography (for example, during restorations, most recently of the Tabernacle of the Linen Drapers) ; research on his production of drawings and miniatures ; and investigations into the resources provided by archival and other documents that throw light onto his activities in both Florence and Rome. Future studies on Fra Angelico will have to avoid the pitfalls of hyper-specialization by bringing together historical, formal, and iconographic elements in a well-informed, holistic approach, perfectly in harmony with the “density” of Fra Angelico’s painting.Dieser Aufsatz zieht eine Bilanz der neueren Studien zu Frau Angelico, indem er die bemerkenswerte Fülle an Publikationen und Ausstellungen über den dominikanischen Künstler in Italien und in anderen Ländern kommentiert. Als Schlüssel­figur des Übergangs vom Mittelalter zur Renaissance bietet Fra Angelico, zugleich thomistischer Theo­loge und früher Interpret des Humanismus’ Albertis, mit seiner Malerei ein fruchtbares Terrain für verschiedene Forschungsrichtungen : Untersuchungen zur Ikonologie und Exegese, wie z. B. die komplexe skripturale und figurative Struktur der Tafeln des Armadio degli argenti (Silberschrank) ; Untersuchungen der Bildquellen seiner Zusammenführung von spätgotischen Stilelementen, Neuheiten der Renaissance und der programmatischen Errichtung des von Giotto definierten Modells ; Untersuchungen zu stilistischen Charakteristika, die den Werkkatalog und seine Chronologie betreffen (wie z. B. im Zuge der Ausstellungen von 2005 in New York und 2009 in Rom) und die sich dabei auf neue Technologien der Diagnostik beziehen wie die Reflektographie mit Infrarotstrahlen (diese wurden u. a. bei Restaurationen angewandt, wie zuletzt des Tabernacolo dei Linaioli (Leinenweber-Altar) ; Studien zum Entstehen der Zeichnungen und der Buchmalerei ; Untersuchungen der archivarischen und dokumentarischen Quellen, die seinen Werdegang in Florenz und Rom beleuchten. Es wäre wünschenswert, dass sich diese Forschungsrichtungen zukünftig von der Überspezialisierung befreien und in ihrer Zusammenführung von historischen, formalen und ikonographischen Elementen eine sehr informierte Sichtweise liefern, die der „Dichte“ der Malerei Frau Angelicos entspricht.Il saggio stila un bilancio degli studi recenti sul Beato Angelico, analizzando la notevole fioritura bibliografica ed espositiva sull’artista domenicano in Italia e all’estero. La pittura dell’Angelico, figura cerniera tra Medioevo e Rinascimento, teologo tomista e insieme precoce inteprete dell’Umanesimo albertiano, offre terreno fecondo per ricerche molteplici : di stampo iconologico ed esegetico, ad esempio sulla complessa intelaiatura scritturale e figurale dell’Armadio degli Argenti ; sulle fonti visive, nella sua sintesi tra preziosità tardogotiche, novità rinascimentali e programmatica emulazione del modello di Giotto ; sulle peculiarità stilistiche, al fine di aggiornarne il catalogo e la cronologia (come nelle mostre di New York del 2005 e di Roma del 2009), anche con l’ausilio di tecnologie diagnostiche quali le riflettografie agli infrarossi (ad esempio in occasione dei restauri, ultimo quello sul Tabernacolo dei Linaioli) ; sulla sua attività di disegnatore e di miniatore ; sulle risorse archivistiche e documentarie, illuminanti la sua attività sia fiorentina che romana. L’auspicio per le ricerche future è di sfuggire l’iperspecialismo, ­contemperando le istanze storiche, formali, iconografiche in una visione aggiornata e consona alla “densità” della pittura angelichiana.El presente ensayo establece un balance de los estudios recientes sobre Fra Angelico, a través de la extraordinaria florescencia de publicaciones y exposiciones dedicadas al artista dominicano, tanto en Italia como fuera de ella. En efecto, la pintura de Fra Angelico, figura eje de la transición de la Edad Media al Renacimiento, teólogo tomista y precoz intérprete del humanismo albertiano, se presta a múltiples investigaciones : estudios iconológicos o exegéticos, de la compleja estructura escrituraria y figurativa del Armario de la plata, por ejemplo ; estudios de las fuentes visuales que conforman su síntesis entre la preciosidad del Gótico tardío, las novedades del Renacimiento y la emulación programática del modelo definido por Giotto ; estudios de sus características estilísticas, a fin de actualizar su catálogo y su cronología (tal como se hizo en las exposiciones organizadas en Nueva York en 2005 y en Roma en 2009), basándose a la par en tecnologías diagnósticas como la reflectografía infrarroja (usada por ejemplo con motivo de restauraciones, siendo la del Tabernáculo de los lineros la última realizada) ; estudios de sus dibujos y de su arte de la iluminación ; estudios de los datos proporcionados por la documentación conservada sobre su actividad tanto en Florencia como en Roma. Es de desear, con vistas al futuro, que dichas investigaciones, escapando de la hyper-especialización, se vean capaces de juntar los elementos históricos, formales e iconográficos, en una visión muy informada, de acuerdo con la “densidad” de la pintura de Fra Angelico

The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

Inhibitors of kinesin spindle protein Eg5 are characterized by pronounced antitumor activity. Our group has recently synthesized and screened a library of 1,3,4-thiadiazoline analogues with the pharmacophoric structure of K858, an Eg5 inhibitor. We herein report the effects of K858 on four different breast cancer cell lines: MCF7 (luminal A), BT474 (luminal B), SKBR3 (HER2 like) and MDA-MB231 (basal like). We demonstrated that K858 displayed anti-proliferative activity on every analyzed breast cancer cell line by inducing apoptosis. However, at the same time, we showed that K858 up-regulated survivin, an anti-apoptotic molecule. We then performed a negative regulation of survivin expression, with the utilization of wortmannin, an AKT inhibitor, and obtained a significant increase of K858-dependent apoptosis. These data demonstrate that K858 is a potent inhibitor of replication and induces apoptosis in breast tumor cells, independently from the tumor phenotype. This anti-proliferative response of tumor cells to K858 can be limited by the contemporaneous over-expression of survivin; consequently, the reduction of survivin levels, obtained with AKT inhibitors, can sensitize tumor cells to K858-induced apoptosis

Infarto Agudo al Miocardio sin Elevación del Segmento ST en Paciente con Neumonía Adquirida en la Comunidad: Caso clínico.

Community-acquired pneumonia and cardiovascular diseases are two entities that represent a high global mortality, and that can act synergistically to hinder the evolution of hospitalized patients. We present the case of a patient with multiple cardiovascular risk factors admitted for a diagnosis of community-acquired pneumonia, complicated by an acute myocardial infarction without ST elevation with atypical symptoms.La neumonía adquirida en la comunidad y las enfermedades cardiovasculares son dos entes que representan una alta mortalidad a nivel global, y que pueden actuar sinérgicamente para entorpecer la evolución del paciente hospitalizado. Se presenta el caso de una paciente con múltiples factores de riesgo cardiovasculares ingresada por diagnóstico de neumonía adquirida en la comunidad, complicada por un infarto agudo al miocardio sin elevación del ST con una clínica atípica

Routes of dispersion of antibiotic resistance genes from the poultry farm system

Poultry farms are hotspots for the development and spread of antibiotic resistance genes (ARGs), due to high stocking densities and extensive use of antibiotics, posing a threat of spread and contagion to workers and the external environment. Here, we applied shotgun metagenome sequencing to characterize the gut microbiome and resistome of poultry, workers and their households - also including microbiomes from the internal and external farm environment – in three different farms in Italy during a complete rearing cycle. Our results highlighted a relevant overlap among the microbiomes of poultry, workers, and their families (gut and skin), with clinically relevant ARGs and associated mobile elements shared in both poultry and human samples. On a finer scale, the reconstruction of species-level genome bins (SGBs) allowed us to delineate the dynamics of microorganism and ARGs dispersion from farm systems. We found the associations with worker microbiomes representing the main route of ARGs dispersion from poultry to human populations. Collectively, our findings clearly demonstrate the urgent need to implement more effective procedures to counteract ARGs dispersion from poultry food systems and the relevance of metagenomics-based metacommunity approaches to monitor the ARGs dispersion process for the safety of the working environment on farms

Punctual and kinetic MRD analysis from the Fondazione Italiana Linfomi MCL0208 phase III trial in mantle cell lymphoma

Minimal residual disease (MRD) analysis is a known predictive tool in mantle cell lymphoma (MCL). We describe MRD results from the Fondazione Italiana Linfomi phase III MCL0208 prospective clinical trial assessing lenalidomide maintenance vs observation after autologous transplantation (ASCT), in the first prospective comprehensive analysis of different techniques, molecular markers, and tissues (peripheral blood, PB, and bone marrow, BM), taken at well-defined timepoints. Among the 300 patients enrolled, a molecular marker was identified in 250 (83%), allowing us to analyze 234 patients and 4351 analytical findings from 10 timepoints. ASCT induced high rates of molecular remission (91% in PB and 83% in BM, by quantitative real-time PCR [RQ-PCR]). Nevertheless, the number of patients with persistent clinical and molecular remission decreased over time in both arms (up to 30% after 36 months). MRD predicted early progression and long-term outcome, particularly from 6 months after ASCT (6-month TTP HR 3.83, p<0.001). In single-timepoint analysis, BM outperformed PB, and RQ-PCR was more reliable, while nested PCR appeared applicable to a larger number of patients (234 vs 176). To improve MRD performance we developed a time-varying kinetic model, based on regularly updated MRD results and the Mantle Cell Lymphoma International Prognostic Index, showing an area under the ROC curve (AUROC) of up to 0.87 using BM. Most notably, PB reached an AUROC of up to 0.81: with kinetic analysis it was comparable to BM in performance. MRD is a powerful predictor over the entire natural history of MCL and suitable for models with continuous adaptation of patient risk. Study can be found in EudraCT N. 2009-012807-25 https://eudract.ema.europa.eu/

Glucokinase Gene Mutations: Structural and Genotype-Phenotype Analyses in MODY Children from South Italy

BACKGROUND: Maturity onset diabetes of the young type 2 (or GCK MODY) is a genetic form of diabetes mellitus provoked by mutations in the glucokinase gene (GCK). METHODOLOGY/PRINCIPAL FINDINGS: We screened the GCK gene by direct sequencing in 30 patients from South Italy with suspected MODY. The mutation-induced structural alterations in the protein were analyzed by molecular modeling. The patients' biochemical, clinical and anamnestic data were obtained. Mutations were detected in 16/30 patients (53%); 9 of the 12 mutations identified were novel (p.Glu70Asp, p.Phe123Leu, p.Asp132Asn, p.His137Asp, p.Gly162Asp, p.Thr168Ala, p.Arg392Ser, p.Glu290X, p.Gln106_Met107delinsLeu) and are in regions involved in structural rearrangements required for catalysis. The prevalence of mutation sites was higher in the small domain (7/12: approximately 59%) than in the large (4/12: 33%) domain or in the connection (1/12: 8%) region of the protein. Mild diabetic phenotypes were detected in almost all patients [mean (SD) OGTT = 7.8 mMol/L (1.8)] and mean triglyceride levels were lower in mutated than in unmutated GCK patients (p = 0.04). CONCLUSIONS: The prevalence of GCK MODY is high in southern Italy, and the GCK small domain is a hot spot for MODY mutations. Both the severity of the GCK mutation and the genetic background seem to play a relevant role in the GCK MODY phenotype. Indeed, a partial genotype-phenotype correlation was identified in related patients (3 pairs of siblings) but not in two unrelated children bearing the same mutation. Thus, the molecular approach allows the physician to confirm the diagnosis and to predict severity of the mutation

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI-GOIM): A randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX

Background: Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. Patients and methods: We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progressionfree survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. Results: Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056]. Conclusions: Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials