19 research outputs found
HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B cell receptor signaling.
No full textBurkitt lymphoma (BL) is an aggressive B cell neoplasm that is currently treated by intensive chemotherapy in combination with anti-CD20 antibodies. Due to their toxicity, current treatment regimens are often not suitable for elderly patients or for patients in developing countries where BL is endemic. Targeted therapies for BL are therefore needed. In this study, we performed a compound screen in 17 BL cell lines to identify small molecule inhibitors affecting cell survival. We found that inhibitors of heat shock protein 90 (HSP90) induced apoptosis in BL cells in vitro at concentrations that did not affect normal B cells. By global proteomic and phosphoproteomic profiling we show that in BL, HSP90 inhibition compromises the activity of the pivotal B cell antigen receptor (BCR)-proximal effector spleen tyrosine kinase (SYK), which we identified as an HSP90 client protein. Consistently, expression of constitutively active TEL-SYK counteracted the apoptotic effect of HSP90 inhibition. Together, our results demonstrate that HSP90 inhibition impairs BL cell survival by interfering with tonic BCR signaling, thus providing a molecular rationale for the use of HSP90 inhibitors in the treatment of BL
AI and Robotics for the City: Imagining and Transforming Social Infrastructure in San Francisco, Yokohama, and Lviv
No full textThis article looks at how existing and planned AI and robotics projects in three cities – San Francisco (United States), Yokohama (Japan), and Lviv (Ukraine) – aim to extend or build social infrastructure to achieve a particular desired vision of city life. The author has chosen contrasting cases both to highlight how particular cultures’ ways of thinking of the human-machine relationship matters for the kind of AI and robotics are envisioned and developed as well as to surface the core characteristics of AI and robotics-supported social infrastructure that transcend cultural, economic, and civic histories. San Francisco houses many of the entrepreneurs, software engineers, and multinationals that create AI and robotics in various markets, including applications for cities. Its proximity and relationship to Silicon Valley provides a “close to home” perspective of AI city imaginaries. Yokohama was selected as Japan’s “Future City” and offers a perspective of government-named and-organized experimentation in the realm of AI and robotics to achieve the so-called “Society 5.0”. Lviv provides a nearly opposite (to Yokohama) example in that the city is in its infancy envisioning how AI may transform its future, and grassroots organization drives the current projects
A Thomistic account of divine providence and human freedom
No full textThis thesis presents a Thomistic account of divine providence and human
freedom. I defend and develop the traditional view by adopting some contemporary
interpretations of it. I argue that the Thomist solution provides an idea that divine
providence is compatible with libertarian freedom.
In the first chapter I provide the definition of divine providence, which is God��������s
continuing action in preserving his creation. In another word, not only does God create
the universe and conserve it in existence at every moment, but he also guides it
according to his purpose.
In the second chapter, I critically examine three solutions to the problem of
providence and human freedom. They are compatibilism, open theism, and Molinism. I
argue that the solutions are unsatisfactory in that they too easily give up some of the
important doctrines concerning God and humans.
In Chapter III, I develop a Thomistic account of divine providence and human
freedom. The Thomistic theory, I argue, well preserves traditional doctrines concerning
both God and humans without damaging either providence or libertarian freedom for
humans. In particular, I briefly examine some characteristics of God, which are
timelessness and his activity as the First Cause. Based on these features of God��������s nature, I show how human beings enjoy entire freedom in the libertarian sense although God has
complete sovereignty over human free choices in the world.
If the present view is correct, what makes it less attractive is that the theory
seems to make God the author of sin. So I finally deal with the problem of moral
responsibility and the problem of evil and sin, showing that humans, not God, are the
author of sin. I contend that God wills that humans sin but he has a certain purpose for
doing so within his providence. But that never destroys human freedom, so humans are
responsible for their decisions and actions. Within the Thomistic explanation we can
have a logically coherent view of compatibility of divine providence with libertarian
freedom of humans. In the last chapter, I summarize my argument and deal with some
implications of it
Textual collisions: the writing process and the Modernist experiment
No full textThis dissertation explores textual junctures such as this in the compositional processes of James Joyce, Djuna Barnes, Mina Loy and Ezra Pound that illuminate how these modernists negotiated the fraught position of being an author in the early twentieth century. This approach marks a departure from conventional textual criticism as I look at the intersections between textual criticism and literary theory, demonstrating the effects different theories can have on our understanding of textual criticism. Recent innovations in textual scholarship influenced by poststructuralist theorists allow me to uncover and describe the extent to which each of these four authors construct a self-conscious version of authorship in relation to their larger Modernist aims. This examination reveals how Joyce, Barnes, Loy, and Pound were subject to numerous outside influences, personal insecurities and preoccupations throughout the writing process, indicating their desires to both manipulate and participate in the modernist project of innovation and experimentation. The first chapter addresses the evolution of Joyce??s pre-writing, drafting and revising processes as a form of textual gossip. Joyce excised material from much of his early writing, controlling his work as a gossiper controls rumors. As he becameincreasingly more inclusive in his writing process, he also reflected a more positive regard for gossip as a similarly inclusive process. The second chapter examines the revision and editing of Ryder, Nightwood, and The Antiphon. Barnes increasingly sought legitimacy for her work by subjecting it to the conventionalizing editing of T.S. Eliot and Emily Holmes Coleman. In the third chapter, I interrogate Pound??s poetic practices and his status as an expatriate in order to reveal how Pound felt as an exile to his own writing. The fourth chapter analyzes Loy??s marginal status in the modernist canon, arguing that she created a persona through her public presentation of herself in her poems that is responsible for her constant and perpetual rediscovery
Hoxa9 and Meis1 cooperatively induce addiction to syk signaling by suppressing miR-146a in acute myeloid leukemia
No full textThe transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia
ABO incompatibile graft management in pediatric transplantation
No full textUp to 40% of donor-recipient pairs in SCT have some degree of ABO incompatibility, which may cause severe complications. The aim of this study was to describe available options and survey current practices by means of a questionnaire circulated within the EBMT Pediatric Diseases Working Party investigators. Major ABO incompatibility (donor's RBCs have antigens missing on the recipient's cell surface, towards which the recipient has circulating isohemagglutinins) requires most frequently an intervention in case of bone marrow grafts, as immediate or delayed hemolysis, delayed erythropoiesis and pure red cell aplasia may occur. RBC depletion from the graft (82%), recipient plasma-exchange (14%) were the most common practices, according to the survey. Graft manipulation is rarely needed in mobilized peripheral blood grafts. In case of minor incompatible grafts (donor has isohemagglutinins directed against recipient RBC antigens), isohemagglutinin depletion from the graft by plasma reduction/centrifugation may be considered, but acute tolerability of minor incompatible grafts is rarely an issue. According to the survey, minor ABO incompatibility was either managed by means of plasma removal from the graft, especially when isohemagglutinin titer was above a certain threshold, or led to no intervention at all (41%). Advantages and disadvantages of each method are discussed.Peer reviewe
The Apostelesse's Social Network: The Meaning of Mary Magdalene in Fifteenth-Century East Anglia
No full textThis dissertation examines how the construction of Saint Mary Magdalene as a symbol participated in a network of political, social, and religious practices in fifteenth- century England. That symbol both changed and was changed by shifting understandings of lay piety. In the second half of the fifteenth century the saint as a symbol became affiliated with the Yorkist side in the War of the Roses in ways that would have repercussions for her interpretation well into the early Tudor period.
Rooted in an analysis of relationships among medieval artifacts and the cultures of their production, my argument employs a synthesis of Actor-Network Theory and Peircian semiotics. This theoretical approach enables my analysis of a network of relationships among individuals, objects, and concepts through which Mary Magdalene travels as a semiotic ���packet��� of linguistic, visual, and conceptual signs. Only part of this packet���s intended information is transferred while it travels through the network, however. This process of change, stemming from differing emphases regarding the saint, allows new ideas to be deliberately added to the packet over time. The author or authors��� immediate needs regarding the saint are always reflected, but elements of previous interpretations of Mary Magdalene���s symbolism remain.
I trace uses of the Middle English term apostelesse throughout the dissertation as a means to follow fifteenth-century ideas regarding Mary Magdalene as they evolve. I begin my analysis of the status of the saint is by considering the interactions of Julian of Norwich���s Revelations of Divine Love, The Book of Margery Kempe, and Nicholas Love���s Mirror of the Blessed Life of Christ. Next, I examine the transplantation of the word into a contemporary, politicized context in Osbern Bokenham���s mid-century Lyf of Marye Mawdelyn. I then turn to the Digby Mary Magdalene play to discuss Mary Magdalene as an apostelesse due to her personal authority and evangelical mission to Marseilles. Finally, the dissertation concludes by noting how the specific changes analyzed in each chapter reflect the changing role of the saint over the course of the fifteenth century and by looking briefly ahead to her symbolism in two early modern works: the Life and Repentaunce of Marie Magdalene and An harborowe for faithful and trewe subiectes
Reviews
No full textC.S. Lewis, Poetry, and the Great War 1914-1918. John Bremer. Reviewed by Joe R. Christopher.
Collected Poems. Hope Mirrlees. Ed. and intro. Sandeep Parmar. Reviewed by Nicholas Birns.
Fantasy, Art and Life: Essays on George MacDonald, Robert Louis Stevenson and Other Fantasy Writers. William Gray. Reviewed by Scott McLaren.
C. S. Lewis and the Middle Ages. Robert Boenig. Reviewed by Holly Ordway.
Sherlock Holmes for the 21st Century: Essays on New Adaptations. Edited by Lynnette Porter. Reviewed by Janet Brennan Croft.
Dancing the Tao: Le Guin and Moral Development. Sandra J. Lindow. Reviewed by Carl Badgley.
Hobbit Place-names: A Linguistic Excursion Through the Shire. Rainer Nagel. Reviewed by Troels Forchhammer.
The Broken Scythe: Death and Immortality in the Works of J.R.R. Tolkien. Edited by Roberto Arduini and Claudio A. Testi. Reviewed by Harley J. Sims.
The Hobbit Tarot. Terry Donaldson (author of guide pamphlet) and Peter Pracownik (artist). Reviewed by Emily A Auger.
The Lord of the Rings Tarot Deck and Card Game. Terry Donaldson (author of guidebook), Peter Pracownik (artist), and Mike Fitzgerald (game rules). Reviewed by Emily A Auger.
J.K. Rowling: Harry Potter. Edited by Cynthia J. Hallett and Peggy J. Huey. Reviewed by Janet Brennan Croft
Cytotoxic capacity of IL-15-stimulated cytokine-induced killer cells against human acute myeloid leukemia and rhabdomyosarcoma in humanized preclinical mouse models
No full textAllogeneic stem cell transplantation (allo-SCT) has become an important treatment modality for patients with high-risk acute myeloid leukemia (AML) and is also under investigation for soft tissue sarcomas. The therapeutic success is still limited by minimal residual disease (MRD) status ultimately leading to patients’ relapse. Adoptive donor lymphocyte infusions based on MRD status using IL-15-expanded cytokine-induced killer (CIK) cells may prevent relapse without causing graft-versus-host-disease (GvHD). To generate preclinical data we developed mouse models to study anti-leukemic- and anti-tumor-potential of CIK cells in vivo. Immunodeficient mice (NOD/SCID/IL-2Rγc−, NSG) were injected intravenously with human leukemic cell lines THP-1, SH-2 and with human rhabdomyosarcoma (RMS) cell lines RH41 and RH30 at minimal doses required for leukemia or tumor engraftment. Mice transplanted with THP-1 or RH41 cells were randomly assigned for analysis of CIK cell treatment. Organs of mice were analyzed by flow cytometry as well as quantitative polymerase chain reaction for engraftment of malignant cells and CIK cells. Potential of CIK cells to induce GvHD was determined by histological analysis. Tissues of the highest degree of THP-1 cell expansion included bone marrow followed by liver, lung, spleen, peripheral blood (PB), and brain. RH30 and RH41 engraftment mainly took place in liver and lung, but was also detectable in spleen and PB. In spite of delayed CIK cell expansion compared with malignant cells, CIK cells injected at equal amounts were sufficient for significant reduction of RH41 cells, whereas against fast-expanding THP-1 cells 250 times more CIK than THP-1 cells were needed to achieve comparable results. Our preclinical in vivo mouse models showed a reliable 100% engraftment of malignant cells which is essential for analysis of anti-cancer therapy. Furthermore our data demonstrated that IL-15-activated CIK cells have potent cytotoxic capacity against AML and RMS cells without causing GvHD
Expansion and maintenance of hematopoietic stem and progenitor cells in course of long-term inhibition of CXCR4/CXCL12 signaling
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