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"Alfred Thomas"
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Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging STAT5BN642H driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor-ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.
Journal Article
Kafka’s Statue: Memory and Forgetting in Postsocialist Prague
This essay is not about Kafka’s Prague – a veritable industry of scholarship – but Kafka’s statue; or rather, what a modern statue of Kafka in postsocialist Prague signifies both about his fate as a writer in the city of his birth and what that fate may tell us about the complex history of twentieth-century Prague and Czechoslovakia. My essay explores how Kafka’s transformation from a largely overlooked writer among the Czech intelligentsia in the 1930s to his belated emergence as the hero of the reformist generation of the 1960s, and from his deliberate erasure by the Soviet-backed regime after the invasion of Prague in 1968 to his reinvention as a national icon following the collapse of Communism in 1989, describes a familiar dialectic between memory and forgetting that has characterized the history of the city in the twentieth century. I argue that Prague’s postsocialist reinvention as the city of Kafka represents neither a radical departure from the past nor the continuation of a specifically Czech tradition of tolerance. I conclude that the city’s latest incarnation as the birthplace of one of European modernism’s greatest writers represents a history of constant reinvention in which political-cultural self-fashioning and economic calculation have all played – and continue to play – an integral role.
Journal Article
التسامح بين شرق وغرب : دراسات في التعايش والقبول بالآخر
يتناول كتاب \"التسامح بين شرق وغرب : دراسات في التعايش والقبول بالآخر\" والذي قام بتأليفه \"سمير الخليل\" وترجمه \"إبراهيم العريس\" في حوالي (127) صفحة من القطع المتوسط موضوع (التسامح بين الشرق والغرب)،اعتبار التسامح في البلدان الديمقراطية أمرا مسلما به، إذ ينظر إلى الفرد مهما اختلف شكلا وسلوكا ولغة، بعين القبول، كما يتوقع منه أن يفعل الشيء نفسه. فإذا ظهر أي ضغط يهدد بتغيير هذا الموقف، اعتبر الأمر خرقا ينطوي على تدمير لحرية الفرد. فنحن نتسامح مع الآخرين ونقبل ما يفعلونه، ما دام إن ذلك لا يرتب أضرارا تصيب المجتمع وأفراده. ذلك إن الاختلاف لا يخلق موقفا يقود إلى التعصب والتقوقع، أما التسامح فمسؤولية حضارية وواحد من حقوق الإنسان. ولئن أدى التقوقع إلى الحؤول دون الاندماج في المجتمع الغريب، يبقى لافتا للنظر أن تخلو الثقافة العربية، السياسي منها والاجتماعي، من مقولة التسامح كلمة وممارسة. لقد لعبت الأيديولوجيات النضالية والقيم السلفية أدوارها في طرد التسامح من حياتنا وثقافتنا. هذا الكتاب يطل على مسألة في العالم الغربي وعند العرب سواء بسواء.
BOOK
MEIS2 Is an Adrenergic Core Regulatory Transcription Factor Involved in Early Initiation of TH-MYCN-Driven Neuroblastoma Formation
Roughly half of all high-risk neuroblastoma patients present with MYCN amplification. The molecular consequences of MYCN overexpression in this aggressive pediatric tumor have been studied for decades, but thus far, our understanding of the early initiating steps of MYCN-driven tumor formation is still enigmatic. We performed a detailed transcriptome landscaping during murine TH-MYCN-driven neuroblastoma tumor formation at different time points. The neuroblastoma dependency factor MEIS2, together with ASCL1, was identified as a candidate tumor-initiating factor and shown to be a novel core regulatory circuit member in adrenergic neuroblastomas. Of further interest, we found a KEOPS complex member (gm6890), implicated in homologous double-strand break repair and telomere maintenance, to be strongly upregulated during tumor formation, as well as the checkpoint adaptor Claspin (CLSPN) and three chromosome 17q loci CBX2, GJC1 and LIMD2. Finally, cross-species master regulator analysis identified FOXM1, together with additional hubs controlling transcriptome profiles of MYCN-driven neuroblastoma. In conclusion, time-resolved transcriptome analysis of early hyperplastic lesions and full-blown MYCN-driven neuroblastomas yielded novel components implicated in both tumor initiation and maintenance, providing putative novel drug targets for MYCN-driven neuroblastoma.
Journal Article
Impacts of the 'Pacific Adventurer' Oil Spill on the Macrobenthos of Subtropical Sandy Beaches
Biological impacts of oil on sandy shore ecosystems remain incompletely understood, especially following smaller spills on subtropical beaches. Here we quantified changes to benthic assemblages on a sandy beach following the 270-t spill of heavy fuel oil from the Pacific Adventurer that occurred in March 2009 off Moreton Island in Eastern Australia. Assessments of ecological impacts are based on spatial contrasts between multiple reference and impact sites sampled 1 week and 3 months after the spill. Benthic invertebrate assemblages exposed to oil had significantly fewer individuals of fewer species 1 week after the spill, markedly changing their ecological structure. Biological differences consistent with oil-related mortality were significant on the lower shore and in the swash and remained so 3 months after the spill. This signals a lack of recovery of these communities in the short term, despite the fairly rapid removal of oil. Results show that, despite the relatively small size of the spill, heavy fuel oil contamination can cause substantial impacts on sandy beach ecosystems, and that recovery may be prolonged.
Journal Article
Anne’s Bohemia
Considers the development of Czech literature and society from the election of Count John of Luxembourg as king of Bohemia in 1310 to the year 1420, when the papacy declared a Catholic crusade against the Hussite reformers. This period is of particular relevance to the study of medieval England because of the marriage of Richard II to Anne of Bohemia, the figure around whom this book is focused.
eBook
Cultures of Forgery
In Cultures of Forgery , leading literary studies and cultural studies scholars examine the double meaning of the word \"forge\"-to create or to form, on the one hand, and to make falsely, on the other.
Alfred Thomas is Professor of Slavic and Baltic Languages and Literatures at the University of Illinois at Chicago and Head of Department. From 1996 to 2002 he was John L. Loeb Associate Professor of the Humanities at Harvard University. He is the author of four books, the most recent of which are Anne's Bohemia: Czech Literature and Society, 1310-1420 (University of Minnesota Press, 1998) and Embodying Bohemia: Questions of Gender and Sexuality in Modern Czech Culture (forthcoming, University of Wisconsin Press, 2004). Judith Ryan is the Robert K. and Dale J. Weary Professor of German and Comparative Literature at Harvard University. She is the author of Umschlag und Verwandlung (on Rilke's poetry; 1972), The Uncompleted Past: Postwar German Novels and the Third Reich (1983), The Vanishing Subject:Early Psychology and Literary Modernism (1991), and Rilke, Modernism and Poetic Tradition (1999). She has also written articles on such authors as Franz Kafka, Paul Celan, Christa Wolf, and Günter Grass. She is currently at work on a book about the relation of the contemporary novel to literary theory.
eBook