Articoli di riviste sul tema "Giraldi, William"

Abstract William Shakespeare’s Othello (1604) displays a critical agenda towards the emerging colonialist discourse of his time and may have encountered, or even been influenced by, African oral literature. This thesis will be probed in this article by comparing Othello with the folktale “The Handsome Stranger” and the Trickster character, well known all across Western Africa, touching lightly on Leo Africanus’s The History and Description of Africa (1550) in the process. In doing so, Othello’s most acknowledged source text, “Un Capitano Moro” by Giovanni Battista Giraldi (1565), will be involved, thus complementing earlier comparative readings of “Un Capitano Moro” and Othello. This postcolonial comparative reading will finally embrace Ahmed Yerima’s adaptation of Othello, entitled Otaelo (2002). In doing so, the article will discuss striking parallels among all four texts, as well as differences and diversions. The latter are, however, not read as counter arguments to the possibility of an encounter; rather, discursive diversions are contextualised historically and trans*textually. Before delving into this analysis, the article will explore both historical probabilities and methodological challenges of reading African oral literature as possible sources of Shakespeare’s Othello, as well as theorise trans*textuality (as related to and yet distinct from Kristeva’s intertextuality and Genette’s transtextuality).This article has developed from two papers, one held in 2015 at a symposium dedicated to Michael Steppat in Bayreuth, who, ever since, accompanied this project with most helpful critical input; I owe him my sincerest gratitude. A second workshop on this topic was held in 2016 in Berlin in the presence of Shankar Raman, Christopher Joseph Odhiambo, and a student research group from Bayreuth with Taghrid Elhanafy, Weeraya Donsomsakulkij, Samira Paraschiv, and Mingqing Yuan. Taghrid Elhanafy dedicates her MA and PhD thesis to comparing Romeo and Juliet with several Arabic and Farsi versions of Layla and Majnun (Cf. Elhanafy 2018). Moreover, this article owes sincere gratitude to a most challenging and expert editing by Shirin Assa, PhD candidate at Bayreuth University, as well as Omid Soltani. Moreover, I wish to thank Dilan Zoe Smida and especially Samira Paraschiv for supporting me while doing research and working on notes and bibliography.

The review is devoted to a book by the philosopher, culturologist, and literary critic René Girard, who famously devised the concept of fundamental anthropology with an emphasis on mimetic violence and scapegoating as cornerstones of social life and culture. His ‘mimetic theory’ constitutes one of the last big narratives of the humanities in the 21st c. A Theater of Envy is a must-read for those interested in Girard’s ‘canon’ and an unconventional interpretation of the English playwright’s oeuvre. The scholar is particularly interested in the Bard’s hypermimetic sensitivity. The book reveals a mimetic dimension in Shakespeare’s works, arguing that the playwright was always drawn to plots with mimetic potential. Following brilliant handling of complex structural models and paradoxical inversions, Shakespeare moved on and gradually lost interest in the mechanics of mimetic rivalry, focusing instead on ethical and human repercussions.

The Girard Crisis of 1957 erupted after a young American serviceman, William S. Girard, shot and killed Mrs. Naka Sakai, a Japanese woman collecting shell cases on an army firing range in Japan. While this incident caused an immediate storm of Japanese protest against American military bases, controversy erupted in the United States only when it was revealed that the Army would waive criminal jurisdiction and hand Girard over to Japanese courts for trial. American press and congressional critics charged that the decision to “surrender” Girard under the provisions of the Status of Forces Agreement (SOFA) threatened the constitutional rights of all American servicemen overseas, while Japan and other Asian countries hotly resented the one-sided SOFAs and lenient treatment of American soldiers in military courts. Secretary of State John Foster Dulles and Secretary of Defense Charles E. Wilson bickered over responsibility, but both worried that the jurisprudential dispute would fatally undermine Japanese support for the Security Treaty and threaten the entire U.S. alliance system in the Far East. Although the administration, with President Eisenhower’s shrewd help, eventually defused the crisis, its initial responses were confused. This article focuses on State Department handling of the diplomatic and jurisdictional issues in Asia and development of a coherent administration strategy in the face of public anger at home.

Abstract Introduction: Gallbladder carcinomas (GBC) are rare and aggressive neoplasms. Previous studies in small GBC cohorts have suggested potential molecular alterations associated with poor prognosis, however, a comprehensive understanding of the recurrent genetic events in this cancer type is very limited. In this study, we aim to characterize in detail the recurrent molecular alterations in GBC and their association with pathologic and clinical characteristics. Material and Methods: We studied the prevalence of somatic mutations and copy number alterations (CNA) in n=244 GBC samples (54% primary, 56% metastatic), collected from 2014 to 2021, and sequenced with the targeted NGS panel MSK-IMPACT. We assessed the correlation of the recurrent genomic variants with several pathologic (e.g., T stage, N stage, grade, histologic subtypes) and clinical characteristics (e.g., clinical stage) using Fisher's exact test. We also used Cox Proportional-Hazards modeling to assess the correlation between genetic variants and patient overall survival (OS). Results: The most common histologic subtypes in this GCB cohort included adenocarcinomas NOS (83%), carcinomas with squamous differentiation (9%), high-grade carcinomas (4%), and carcinomas with neuroendocrine differentiation (3%). Most patients were diagnosed with stage IV (65%) and stage III (11%) disease at the time of biopsy/resection, and the mean OS survival was 29.4 months. The most commonly mutated genes were TP53 (59%), SMAD4 (21%), ARID1A (19%), PIK3CA (10%), KRAS (7%), and ERBB2 (7%). Potentially recurrent oncogenic CNAs included deep deletions in CDKN2A (14%) and CDKN2B (14%), and amplifications in MDM2 (12%), ERBB2 (10%), CCNE1 (9%), MYC (7%), and KRAS (7%). RB1, PBRM1, and CTNNB1 variants were more common in cases with neuroendocrine differentiation, whereas alterations in IKZF1 and AGO2 were enriched in cases with squamous differentiation. The most significant event associated with shorted OS was chromosome 12q13-15 amplification i.e., CDK4 p=0.03 HR=2 [95% CI 1-3.6] and MDM2 p=0.05 HR=1.6 [1-2.5], which associated with a median OS of 20 months (vs. 34 months in the wild-type). Genomic variants associated with longer OS included ERBB2 (p=0.006 HR=0.2 [0.06-0.6]), KMT2C (p=0.03 HR=0.2 [0.1-0.9]) and KMT2D (p=0.01 HR=0.2 [0.04-0.7]) mutations, and CDK12 amplification (p=0.04 HR=0.4 [0.2-0.96]). Although ERBB2 amplification was not associated with prognosis, co-amplification of CDK12 and ERBB2 (chromosome 17q12) was frequently observed (Pearson correlation r=0.8). Conclusions: This large-scale genomic analysis reveals recurrent genomic events potentially associated with prognosis in GBC, including single nucleotide variants in ERBB2, KMT2C, and KMT2D, in addition to CNAs in chromosome 12q13-15 and 17q12 regions. This effort will continue to include a detailed analysis of recurrent structural variants, loss of heterozygosity loci, and analysis of the microbiota in this GBC cohort. Citation Format: Nicolas A. Giraldo, Abhinita Mohanty, Chad Vanderbilt, Rose Brannon, Ryma Benayed, Efsevia Vakiani, Ghassan Abou-Alfa, James Harding, Imane El Dika, Nikolaus Schultz, Bob Li, Michael F. Berger, Marc Ladanyi, Eileen O'Reilly, William Jarnagin, Olca Basturk, Maria Arcila. Molecular characterization of gallbladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 82.

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GARCÍA-PRADA CAMILO) I-28 HISTOPLASMOSIS PERITONEAL EN UN PACIENTE INMUNOCOMPROMETIDO (SIERRA UMAÑA SEBASTIÁN FELIPE, ROSERO PAREDES SILVIO JAVIER, URRUTIA CORREDOR LAURA CAMILA, BARRIOS VILLEGAS JUAN ESTEBAN, ARCE CUERVO JULIANA) I-29 PRESENTACIÓN INUSUAL DE CRIPTOCOCOSIS CEREBRAL COMO LESIÓN TUMORAL INTRACRANEAL EN PACIENTE CON ANTECEDENTE DE GLIOBLASTOMA CEREBRAL (REYES TOLEDO RAÚL, MESA ZULUAGA MARIA, GÓMEZ QUINTERO CARLOS, RIVAS PILAR) I-30 EMPIEMA PLEURAL POR SALMONELLA EN PACIENTE CON LUPUS ERITEMATOSO SISTÉMICO (CONTRERAS ALEJANDRA, NOVOA DANNY) I-31 RECIDIVA DE LEPRA, EN PACIENTE INICIALMENTE DIAGNOSTICADO CON DERMATITIS EXFOLIATIVA ASOCIADA A MEDICACIÓN ANTITUBERCULOSA (MESA ZULUAGA MARÍA ALEJANDRA, MEDINA AHUMADA PATRICIA) I-32 MICOBACTERIA DE CRECIMIENTO RÁPIDO EN UN PACIENTE CON USO DE ANTI-TNF (GUTIÉRREZ-BOLAÑOS JOHANN, VARELA DIANA-CRISTINA, GARCÍA-RINCÓN CRISTIAN-IVÁN) I-33 PARACOCCIDIOIDOMICOSIS COMO CAUSA DE INSUFICIENCIA SUPRARRENAL, UN RETO DIAGNOSTICO PARA UNA 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UNA TRIADA POCO USUAL (GUERRA HAROL, BRICEÑO OSCAR, CORTES CAMILO) I-56 EMPIEMA NECESSITATIS POR ENTEROBACTERIAS (SALINAS-CORTES DIEGO FERNANDO, PERDOMO DANIELA, SALAMANCA-MONTILLA JHON F, MONDRAGÓN-CARDONA ALVARO) I-57 ASPERGILOSIS PULMONAR INVASIVA EN PACIENTE INMUNOCOMPETENTE (MEDINA AHUMADA PATRICIA, HERNÁNDEZ DANIEL) I-58 INFECCIÓN POR VARICELA ZOSTER DISEMINADA COMPLICADA CON HEPATITIS EN PACIENTE INMUNOCOMPETENTE (MEDINA AHUMADA PATRICIA, HERNÁNDEZ DANIEL) I-59 OSTEOMIELITIS DEL PUBIS (SIERRA UMAÑA SEBASTIÁN FELIPE, MUÑOZ ROSSI FELIPE ALEJANDRO, CASTILLO RODRÍGUEZ CRISTIAN ALEJANDRO, SALINAS MENDOZA SEBASTIAN, ALVEAR REALPE JONATHAN AMBROSIO, LÓPEZ DONATO DIEGO FERNANDO)

Frank Witzels Roman Direkt danach und kurz davor1 beginnt mit einem kurzen Vorspann, der suggeriert, eine Geschichte zu erzählen. Aus kindlicher Perspektive wird der Umriss einer namenlosen Stadt in der unmittelbaren Nachkriegszeit skizziert (,,Trümmern“, ,,nicht komplett dem Erdboden gleichgemacht“, 9) – einem verschwommenen Gemälde Gerhard Richters aus seiner Unschärfe-Periode gleich (die Unschärfe-Kategorie wird vom Erzähler – wer spricht? – wiederholt kommentiert, z.B.: ,,Bezieht sich die Unschärfe auf den ungenauen Vorgang des Erinnerns?“, 42); und tatsächlich spielen Gemälde, Bilder, eine (nicht nur) parodistische Rolle im Roman (der junge Siebert als ,,Dokumentenmaler“ in der ,,Villa“ des alten Siebert). Die Familie des Jungen wird angedeutet, die Wohnsituation in der Nachkriegszeit (,,Wohnküche“, 14; ,,Wohnungstür ohne Schloss“, 13), das Zerbrechen aller Traditionen (,,Gebräuche“, 7), vor allem der religiösen (,,Begann das Kreuzzeichen wirklich an der Stirn?“, 7): das alles schafft eine Atmosphäre der Ungewissheit und Orientierungslosigkeit. Die Religion ist ,,dem Numinosen im Alltag“ (15) gewichen, und zwar dem Drops, der zugleich ,,die Dreifaltigkeit“ (15), ,,Verheißung und Erfüllung“ (14) ist. In mythisch-religiöses Licht gehüllt, wird ein Mädchen in der Kirche wie eine Epiphanie evoziert; sie trägt ein ,,makellos“ weißes Kleid, das plötzlich einen roten Fleck zeigt, der sich als Lippenstift entpuppt: Reinheit, Unschuld und verdrängte Blutschuld (Schminke) sind hier in einem Symbol verdichtet, das den ganzen Roman durchziehen wird und dem immer neue Bedeutungen im Sinne der Derrida‘schen différance aufgepfropft werden.2 Die Gräueltaten der Nazis, die Namen der Täter, die Besatzungsmächte werden ganz selten direkt benannt (das gilt auch für ,,typische“ Phänomene der Nachkriegszeit wie z.B. ,,Westermanns Monatshefte“, 243); der Roman streut quasi kleine Bruchstücke, informative Splitter aus, die immer zugespitzter werden. Er montiert Bilder, Allegorien (dazu später), Symbole im Sinne der literarischen Montage Benjamins, um die unvorstellbar grausamen Geschehnisse der Nazizeit, die ja in der Nachkriegszeit fortleben bis heute, dem Vergessen und Verdrängen zu entreißen. Witzel überträgt auf den Roman und seine Tropen den Versuch Walter Benjamins, das ,,Prinzip der Montage in die Geschichte zu übernehmen. Also die großen Konstruktionen aus kleinsten, scharf und schneidend konfektionierten Baugliedern zu errichten. Ja in der Analyse des kleinsten Einzelmoments den Kristall des Totalgeschehens zu entdecken. Also mit dem historischen Vulgärnaturalismus zu brechen.“3 So wird das besudelte Symbol der Unschuld und Reinheit, das weiße Kleid, transformiert zum allegorischen ,,Bluttuch“, das auch schon mal auf dem ,,Jahrmarkt“ als Attraktion gezeigt wird (123) – die Bedeutungsschichten der Wörter vibrieren; angeblich war es von einem Geschwisterpaar (Marga und Siebert?) auf dem Narthalerfeld gefunden worden, wohin die beiden Kinder liefen, weil dort ein Flugzeug abgestürzt war; dem toten (?) Piloten lösten sie das blutige Halstuch und nahmen es mit. Mit dem Bluttuch verbinden sich Aberglaube und Volksglaube in Anlehnung an deutsche Mythen wie dem von den Nazis propagandistisch missbrauchten Nibelungenlied (es macht ,,unverwundbar“, 125). Aber, so die kommentierende Erzählerstimme: ,,Alles erscheint in zweierlei Form“ (129), und, da alles ungewiss, geheimnisvoll und vage bleibt, folgt: ,,Auch das Bluttuch?“ Und ob. Mit ihm verbindet sich nicht nur der Begriff, die abstrakte Idee der Reinheit im allegorischen Bild, sondern auch die Idee des ,,unschuldige[n] Vergessen[s]“: ,,Die Verbindung von Unschuld mit dem gleichzeitigen Verlust der Unschuld – nichts anderes symbolisiert das Bluttuch. Um nichts anderes geht es: Das Vergehen der Unschuld im Moment ihres Entstehens“ (129). Die différance, die hier wirksam ist in ihrem unendlichen Bedeutungsaufschub, lässt das Bluttuch auch auf einem Gemälde erscheinen, wo es Marga ziert, die mit dem Piloten vermeintlich verlobt war, sodass das Tuch jetzt schlicht ,,ewige Treue“ symbolisiert (195). Das Bluttuch taucht schließlich auch in den Anmerkungen zu den drei Siebert’schen Märchen aus der Sammlung von Frau Siebert (Frau des alten Professor Siebert) auf – die Märchen werden hervorgehoben, im Sinne der Aphorismen des Novalis’schen Allgemeinen Brouillon, als vollkommen realistisch zu lesende (340). Vielleicht eine verdeckte Leseanleitung für den gesamten Roman? Das Motiv von imaginärer Reinheit, Unschuld und verdrängter Schuld verdichtet sich schließlich in der Erwähnung des Bildes, das der ,,Dokumentenmaler“ Siebert im Hause des alten Siebert nie gemalt hat (sic!): der Straße im Schnee ohne Menschen. Dem entspricht das Lacan‘sche Imaginäre der gesellschaftlichen Ordnung der narzisstisch agierenden BRD, die gerne solch ein Bild der Unschuld von sich gemalt gehabt hätte, dem der junge Siebert sich aber verweigert. Am eindringlichsten erscheint die Symbolik des ideologisch motivierten Tötens bei gleichzeitiger Verweigerung der Annahme der Schuld in dem Kapitel ,,Ein Beispiel aus dem Bibelkommentar der Krötenkinder“ (437ff). Die Exegese bezieht sich auf 2. Mo 23:19: ,,Du sollst das Böcklein nicht kochen in seiner Mutter Milch“. Im psychoanalytischen Deutungsansatz (das Lacan’sche Spiegelstadium) wird mit dem Verbot – und jedes ,,Verbot“ verweist auf die ,,Existenz des Verbotenen“ (437) – auf das Sterben von Mutter und Kind aneinander in dem ,,Gefangensein[…] in einer familiären Struktur“ (438) abgehoben. Indem aber das Kind mit der Muttermilch nicht genährt, sondern im Gegenteil getötet wird (man denke an Celans ,,Schwarze Milch der Frühe“), der Leib des Tieres als Aas (unrein) – ausgenommen der Leib Christi im NT –, sein Blut hingegen als rein angesehen wird, kommt das obige Verbot einer ,,Aufforderung zum Töten“ (438) gleich. Das Böcklein wird ,,zu einer Projektionsfläche der gesellschaftlichen und familiären Zusammenschlüsse, die […] allein noch aus wirtschaftlich-politischen Gründen existieren. Gleichzeitig wird von langer Hand das Bild vom Lamm Gottes entworfen […]. Der Herr war durch seine Schlachtung rein und heilig geworden“ (438). Bei dieser biblischen Allegorese, die Witzel zugleich übernimmt und in ihrer Bedeutung verschiebt, ist mit dem ,,Herrn“ ein Sündenbock im Sinne Lacans (und René Girards) gefunden, der zum einen jede Sünde auf sich nimmt, der aber (und dem) gerade deshalb – des reinen Blutes wegen – geopfert werden muss: die Erlösung als narzisstische Reinwaschungs-Projektion von jedweder Schuld. Die biblisch-mythologische Ebene dient hier als Mikrostruktur, in der die gesellschaftliche Makrostruktur aller Zeiten gespiegelt wird, ein mise en abyme, als das man auch die psychoanalytische Deutung selbst betrachten könnte, die der Roman ja mitliefert, also gleichsam ein doppeltes mise en abyme. Witzel erzählt also keine chronologische Geschichte (,,Beginnt die Lüge nicht mit der Konstruktion der Erzählung?“, 518 – was natürlich nicht nur für das ,,realistische“ Erzählen gilt), sondern zerstört, wie die metasprachlich-selbstreflexive Ebene des Romans auch kommentiert, das lineare (epische) Modell, das der Erzähl-Ontologie der Repräsentation gehorcht, zugunsten des Derrida’schen allgemeinen Textes, der jede ,,diskursive Ordnung“ (Gesetz, Sinn, Wahrheit, Logos, Bewusstsein etc.) ,,überschreitet“4, und dem sich alles sogenannte Wirkliche, z.B. die historischen Anspielungen an den Nationalsozialismus und die unmittelbare Nachkriegszeit (78, 244, 273, 284 u.a.), die philosophischen Bezüge, die intertextuellen Verweise, die realen Namen etc., nur hinzufügt: ,,Selbst wenn die Lektüre sich nicht mit der Verdoppelung des Textes begnügen darf, so kann sie […] auch nicht über den Text hinaus- und auf etwas anderes als sie selbst zugehen, auf einen Referenten (eine metaphysische, historische […] Realität […]). Ein Text-Äußeres gibt es nicht.“5 Das bedeutet auch, dass jeder ,,Referent“ ebenso Text im Derrida‘schen Sinne ist, sodass der vermeintliche Dualismus von Literatur (Fiktion) und Geschichte (Fakten) aufgehoben ist. Welche Funktion kommt, nach all diesen Überlegungen, dem Vorspann des Romans zu? Der vermeintliche ,,Realismus“ der fiktiven Stadt wird im Roman selbst variiert, ins Erzähltheoretische einerseits (die ,,Stadt als Text“, 189), ins Symbolische bzw. Allegorische andererseits transformiert; es gibt einen ,,Gründungsmythos der Stadt“, wobei die ,,Stadt“ eine allegorische Dimension annimmt und zum Bild der Zeit nach Krieg und Holocaust wird (Krieg und Holocaust gelten als ,,mystisches Zeitalter“); durch ihre totale ,,Erinnerungslosigkeit“ haben die Bewohner der ,,Stadt“ einen ,,theo-nihilistischen Zustand, dies[e] Nichtung des Menschen durch Gott“ herbeigeführt (399), sodass die Menschen nun wiederum die ,,Hoffnung auf eine Wiederkehr des Gründers, der die Stadt aus ihrem grauen Dahingeworfensein befreien“ würde (469), hegen und erneut deutlich wird, dass die neue die alte Ordnung wenn nicht ,,ist“, so doch im Kern in sich trägt. Die ,,Erinnerungslosigkeit“ als Auslöser der existentialistisch-nihilistischen Gestimmtheit wird am Beispiel des Briefes an den Schüler Ralph Fählmann im Vorspann besonders deutlich. Raph Fählmann starb mit vierzehn Jahren an den grauenvollen Experimenten der Nazis an den Kindern des Waisenhauses der Stadt (295), seine Geschichte wurde aber später vertuscht, verschwiegen und umgeschrieben (302ff) – das Vertuschen, Verschweigen, ,,Bereinigen“ als der ,,Gründungsmythos der Stadt“. Der Schüler Ralph Fählmann wohnte offenbar einst in dem Haus, in dem nun die Familie des Jungen wohnt, aber als der unzustellbare Brief kommt, fragt niemand nach, die Eltern schweigen, die Kinder erfinden lustige Geschichten, die sich um den Brief ranken. Das genau ist die ,,Stimmung“ der Zeit und ihrer Menschen, die sich allerdings auch heute noch findet (,,The past is never dead. It’s not even past“ – wir haben William Faulkner im Kopf). Die Menschen ,,waren einfältig“, kommentiert eine Erzählerstimme (wer spricht?), ,,hatten alles geglaubt, was man ihnen vorgegeben hatte“; und auch für die Ereignisse (z.B. den Brief an Ralph Fählmann) ,,spürten sie keine Neugierde, sondern nur eine der vielen Varianten von Gleichgültigkeit“ (16). Was hier im Vorspann schon angesprochen wird, durchzieht den gesamten Roman als Heidegger’sche ,,Gestimmtheit“, als (nie gehörten) ,,Ruf des Gewissens“ (,,Liegt im Gerufenwerden nicht etwas Anheimelndes […]? Ist das Gerufenwerden nicht konstitutiv für jede neue entstehende Gesellschaft?“, 50) und ebenso als Krankheit des jungen Siebert und Flucht in die alte Existenzphilosophie (Kierkegaard, Sartre, Heidegger, Camus) und Entwurf einer neuen (99). Aber es gilt ja, und auch im Roman wird es in vielen Variationen immer wiederholt, dass die neue Ordnung zugleich die alte ist (keine saubere Dichotomie von alt vs. neu), und auch das Re-Edukationstheater (223ff.) ändert nichts an diesem Gefühl des ,,Na, da sind wir noch einmal mit einem blauen Auge davongekommen“ (16) – bei Thornton Wilder hieß das 1942 ,,Through The Skin Of Our Teeth“. Bei Hans Ulrich Gumbrecht, der sich in seinem Buch Nach 1945 in vielen existentialistischen Texten (Philosophie, Theater u.a.) dem Begriff der ,,Stimmung“ widmet, heißt es:

Abstract Clonal evolution of DCIS to invasion Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5-10%) of DCIS patients develop subsequent invasive breast cancer (IBC). If not treated, at least 3 out of 4 women with DCIS will not develop IBC1-3. This implies many women with non-progressive, low-risk DCIS are likely to carry the burden of overtreatment. To solve this DCIS dilemma, two fundamental questions need to be answered. The first question is, how the subsequent IBC is related to the initial DCIS lesion. The second question is how to distinguish high- from low-risk DCIS at the time of diagnosis. This is essential to take well-informed DCIS management decisions, i.e., surgery, followed by radiotherapy in case of breast conserving treatment with or without subsequent endocrine treatment, or test whether active surveillance for low-risk DCIS is safe. How is the subsequent IBC related to the initial DCIS? The high genomic concordance in DNA aberrations between DCIS and IBC suggest that most driver mutations and CNA events are acquired at the earliest stages of DCIS initiation. It has therefore been assumed that most solid tumours arise from a single cell and that the probability of two independent tumours arising from the same tissue is low4-6. However, lineage tracing and genomic studies strongly suggest both direct and independent clonal lineages during the initiation of DCIS and evolution to IBC. In these processes, mammary stem cells have been implicated in DCIS initiation. Role of mammary stem cells in DCIS initiation Lineage tracing mouse model experiments have shown the fate of individual cells and lineages that acquire mutations before a tumour is established7-9. This is also relevant for DCIS initiation10,11, as different pools of MaSCs drive the growth and development of the ductal network and are considered the cell of origin for breast cancers9,10. The ductal trees remain quiescent until puberty, during which extension, branching and termination of terminal end buds (TEBs) leads to its expansion throughout the fat pad7,12,13. Any oncogenic mutation that occurs in a fetal MaSC will spread throughout the ductal network to a large part of the ductal tree, leading to sick lobes9. By contrast, oncogenic mutations acquired by a single MaSC during puberty spread to a smaller number of offspring located in small clusters in a part of the ductal network8,14. Direct lineage models for DCIS progression Direct lineage models postulate that DCIS has a single cell of origin that acquires mutations and progresses to IBC15-18. This is also supported by the high genomic concordance of CNAs and mutations in synchronous DCIS–IBC regions6,15,17,19-21 and the results of a recent large longitudinal study that profiled pure DCIS and recurrent IBC using multiple sequencing techniques, which estimated direct clonal lineages in approximately ~80% of patients18. Two distinct direct lineage models have been proposed: the evolutionary bottleneck model and the multiclonal invasion model. In the evolutionary bottleneckmodel, a single clone (or a limited number of clones) with an invasive genotype is selected and breaks through the basement membrane to migrate into surrounding tissues15,16,22, while other clones are unable to escape the ducts21-28. The multiclonal invasion model posits that most or all subclones can escape the basement membrane, establishing invasive disease6,16,17,20. The multiclonal model has not been studied widely in pure DCIS and recurrent IBC samples. Independent lineage model for DCIS progression DCIS lesions and IBCs can arise from different initiating cells in the same breast independently5,20,29-32. An analysis of sequential DCIS–IBC pairs in a unique, large-scale, in-depth study of 95 matched pure DCIS and recurrent IBC showed that ~20% of the IBC recurrences were indeed clonally unrelated to the primary DCIS18, as is also supported by some mathematical model studies33. The potential role of a field effect IBC can develop in the same breast as an initial DCIS even after treatment, which could be explained by the presence of a field effect34-37. Alternatively, the sick lobe hypothesis proposes that a single lobe harbours first-hit mutations, acquired in utero or during early mammary development37-42. This could also explain the restriction of IBC to the ipsilateral side of the breast39,43,44. Germline mutations may also explain the emergence of independent lineages in DCIS and IBC patients, lowering the threshold for cancer development32,43-46. Convergent evolution model of DCIS progression A third model for the emergence of IBC from DCIS is convergent evolution, in which the same mutations and CNA are selected and expanded during tumour growth such that environmental factors fuel competition between distinct clones and push them towards a similar genotype. Ultimately, two independent clonal lineages from different ancestral cells then happen to share multiple genomic aberrations or driver mutations across regions47-49. Although independent lineages are considered uncommon (~20%) in ipsilateral recurrences, they occur at much higher frequencies in contralateral recurrences (>80%), in which single-nucleotide polymorphism and comparative genomic hybridization microarrays show few (or no) genomic alterations shared in tumours from the contralateral breast cancer18,50,51. How to distinguish high- from low-risk DCIS at the time of diagnosis? The genomic and transcriptomic profile present at the time of DCIS diagnosis may contain crucial information on the risk of progression of DCIS to IBC. Thus far, it has been unclear whether prognostic gene expression markers can be used to separate indolent DCIS from potentially progressive DCIS. To this end, microarrays and RNA-seq have been applied for the comparison of bulk RNA from microdissected DCIS and IBC tissue. In synchronous DCIS–IBC, a limited number of transcriptional differences have been found and the few events discovered often varied extensively across different tumours52-56. Although these differences were strong, the added value of these studies is uncertain as they are often confounded by small sample size, lack of matched receptor status data, and low sample purity. Despite these limitations, these studies have implicated the epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) remodelling pathways as potentially relevant for the progression of DCIS to IBC55-62. We studied two large DCIS cohorts: the Sloane cohort, a prospective breast screening cohort from the UK (median follow-up of 12.5 years), and a Dutch population-based cohort (NKI, median follow-up of 13 years). FFPE tissue specimens from patients with pure primary DCIS after breast-conserving surgery (BCS) +/- RT that did develop a subsequent ipsilateral event (DCIS or invasive) were considered as cases, whereas patients that did not develop any form of recurrence up to the last follow-up or death were considered as controls. We performed copy number analysis (CNA) and RNAseq analysis on 229 cases (149 IBC recurrences and 80 DCIS recurrences) and 344 controls. We classified DCIS into the PAM50 subtypes using RNAseq data which revealed an enrichment of luminal A phenotype in DCIS that did not recur (P = 0.01, Fisher Exact test). No single copy number aberration was more common in cases compared to controls. RNAseq data did not reveal any genes significantly over/under expressed in cases versus controls after false discovery rate (FDR) correction. However, by limiting the analysis to samples that had not had RT and excluding pure DCIS recurrences we developed a penalized Cox model from RNAseq data. The model was trained on weighted samples (to correct for the biased sampling of the case control dataset) from the NKI series with double loop cross validation. Using this predicted hazard ratio, the samples were split into high, medium and low risk quantiles, with a recurrence risk of 20%, 9% and 2.5%, respectively at 5 years (p<0.001, Wald test). The NKI-trained predictor was independently validated in the Sloane No RT cohort (p = 0.02, Wald test). GSEA analysis revealed proliferation hallmarks enriched in the recurrence predictor (FDR = 0.058). The NKI-RNAseq predictor was more predictive of invasive recurrence than PAM50, clinical features (Grade, Her2 and ER) and the 12-gene Oncotype DCIS score (p < 0.001, permutation test using the Wald statistic) in both the NKI and Sloane series. In the methylation analysis, 50 controls were compared with 35 cases. We could identify Variably Methylation Regions (VMRs) and Differentially Methylated Regions (DMRs) between cases and controls. Interestingly, VMRs were enriched in cell adhesion pathways Conclusion The recently acquired knowledge described above on how often the subsequent IBC is directly related to the initial DCIS and on molecular markers predicting the risk of DCIS progression is essential for accurate DCIS risk assessment. 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Background: The use of cytokine-blocking agents has been proposed to modulate the inflammatory response in patients with COVID-19. Tocilizumab and anakinra were included in the local protocol as an optional treatment in critically ill patients with acute respiratory distress syndrome (ARDS) by SARS-CoV-2 infection. This cohort study evaluated the effects of therapy with cytokine blocking agents on in-hospital mortality in COVID-19 patients requiring mechanical ventilation and admitted to intensive care unit.Methods: The association between therapy with tocilizumab or anakinra and in-hospital mortality was assessed in consecutive adult COVID-19 patients admitted to our ICU with moderate to severe ARDS. The association was evaluated by comparing patients who received to those who did not receive tocilizumab or anakinra and by using different multivariable Cox models adjusted for variables related to poor outcome, for the propensity to be treated with tocilizumab or anakinra and after patient matching.Results: Sixty-six patients who received immunotherapy (49 tocilizumab, 17 anakinra) and 28 patients who did not receive immunotherapy were included. The in-hospital crude mortality was 30,3% in treated patients and 50% in nontreated (OR 0.77, 95% CI 0.56-1.05, p=0.069). The adjusted Cox model showed an association between therapy with immunotherapy and in-hospital mortality (HR 0.40, 95% CI 0.19-0.83, p=0.015). This protective effect was further confirmed in the analysis adjusted for propensity score, in the propensity-matched cohort and in the cohort of patients with invasive mechanical ventilation within 2 hours after ICU admission.Conclusions: Although important limitations, our study showed that cytokine-blocking agents seem to be safe and to improve survival in COVID-19 patients admitted to ICU with ARDS and the need for mechanical ventilation. *Modena Covid-19 Working Group (MoCo19): Intensive Care Unit: Massimo Girardis, Alberto Andreotti, Emanuela Biagioni, Filippo Bondi, Stefano Busani, Giovanni Chierego, Marzia Scotti, Lucia Serio, Annamaria Ghirardini, Marco Sita, Stefano De Julis, Lara Donno, Lorenzo Dall’Ara, Fabrizio Di Salvo, Carlotta Farinelli, Laura Rinaldi, Ilaria Cavazzuti, Andrea Ghidoni, Antonio Buono, Elena Ferrari, Daniela Iseppi, Anna Maria Ardito, Irene Coloretti, Sophie Venturelli, Elena Munari, Martina Tosi, Erika Roat, Ilenia Gatto, Marco Sarti.Immuno-Lab: Andrea Cossarizza, Caterina Bellinazzi, Rebecca Borella, Sara De Biasi, Anna De Gaetano, Lucia Fidanza, Lara Gibellini, Anna Iannone, Domenico Lo Tartaro, Marco Mattioli, Milena Nasi, Annamaria Paolini, Marcello Pinti. Infectious Disease Unit: Cristina Mussini, Giovanni Guaraldi, Marianna Meschiari, Alessandro Cozzi-Lepri, Jovana Milic, Marianna Menozzi, Erica Franceschini, Gianluca Cuomo, Gabriella Orlando, Vanni Borghi, Antonella Santoro, Margherita Di Gaetano, Cinzia Puzzolante, Federica Carli, Andrea Bedini, Luca Corradi. Respiratory Diseases Unit: Enrico Clini, Roberto Tonelli, Riccardo Fantini, Ivana Castaniere, Luca Tabbì, Giulia Bruzzi, Chiara Nani, Fabiana Trentacosti, Pierluigi Donatelli, Maria Rosaria Pellegrino, Linda Manicardi, Antonio Moretti, Morgana Vermi, Caterina Cerbone.Virology and Molecular Microbiology Unit: Monica Pecorari, William Gennari, Antonella Grottola, Giulia Fregni Serpini.