The Poetry Of A M Klein

This thesis is devoted to a full explication of the poetry of A. M. Klein. Klein\u27s unpublished and uncollected work, almost all of it located in the Public Archives of Canada, as well as his published poetry volumes (Hath Not a Jew..., Poems (1944), The Hitleriad, The Rocking Chair and Other Poems), are discussed in detail. The thesis begins with Klein\u27s earliest unpublished efforts in the mid to late \u27twenties and advances chronologically through to 1948 and the Governor General Award-winning Rocking Chair volume.;It is the author\u27s thesis that Klein\u27s poetry consistently and masterfully represents the central conflict of modernism: the struggle to find order in a fragmented universe. Klein\u27s quest for meaning assumes special resonance in the light of the Jewish burden of identity, isolation, and assimilation in the twentieth century. In the rich Talmudic and Kabbalistic traditions of his Jewish inheritance, with its insistence on the ordering properties of language, Klein finds a nourishing source of moral and aesthetic inspiration. Considerable attention is devoted to Klein\u27s innovatively expressive use of formal poetic devices.;The thesis also relies on Klein\u27s editorial work (for the Judaean and the Canadian Jewish Chronicle) and on an unfinished, unpublished prose manuscript, The Golem, to illuminate Klein\u27s central moral-aesthetic considerations, particularly the poet\u27s relationship to a creative God. In Klein\u27s romantic view of his craft, the poet imitates the first act of creation every time that he puts pen to paper. The act of writing is a necessary act of ordering. That the poet\u27s creative accomplishments may go unheeded and unnoticed in his own age is a sign of both the limitations of that age and the inevitable consequence of the poet\u27s condition. This theme finds its fullest expression in the splendid Portrait of the Poet as Landscape, the concluding poem of both The Rocking Chair volume and this thesis. As a whole, The Rocking Chair and Other Poems represents Klein at his most elegant and accomplished. The poems of that volume are distinguished by a fitting and graceful suspension of tensions, such as subject and object, form and content, poet and landscape, past and present, interior and exterior space. (Abstract shortened with permission of author.

MiR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2

Myelofibros is (MF) is a myeloproliferative neoplasm characterized by cytopenia and extramedullary hematopoiesis, resulting in splenomegaly. Multiple pathological mechanisms (e.g., circulating cytokines and genetic alterations, such as JAK(V617F) mutation) have been implicated in the etiology of MF, but the molecular mechanism causing resistance to JAK(V617F) inhibitor therapy remains unknown. Among MF patients who were treated with the JAK inhibitor ruxolitinib, we compared noncoding RNA profiles of ruxolitinib therapy responders versus nonresponders and found miR-S43 was significantly upregulated in non responders. We validated these findings by reverse transcription-quantitative PCR. in this same cohort, in 2 additional independent MF patient cohorts from the United States and Romania, and in a JAK2(V617F) mouse model of MF. Both in vitro and in vivo models were used to determine the underlying molecular mechanism of miR-543 in MF. Here, we demonstrate that miR-543 targets the dioxygenases ten-eleven translocation 1 (TET1) and 2 (TET2) in patients and in vitro, causing increased levels of global 5-methylcytosine, while decreasing the acetylation of histone 3, STAT3, and tumor protein p53. Mechanistically, we found that activation of STAT3 by JAKs epigenetically controls miR-543 expression via binding the promoter region of miR-543. Furthermore, miR-543 upregulation promotes the expression of genes related to drug metabolism, including CYP3A4, which is involved in ruxolitinib metabolism. Our findings suggest miR-543 as a potentially novel biomarker for the prognosis of MF patients with a high risk of treatment resistance and as a potentially new target for the development of new treatment options

MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199

Targeted therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of current research. Mixed Lineage Leukemia (MLL) mutations such as the t(4;11) translocation cause aggressive leukemias that are refractory to conventional treatment. The t(4;11) translocation produces an MLL/AF4 fusion protein that activates key target genes through both epigenetic and transcriptional elongation mechanisms. In this study, we show that t(4;11) patient cells express high levels of BCL-2 and are highly sensitive to treatment with the BCL-2-specific BH3 mimetic ABT-199. We demonstrate that MLL/AF4 specifically upregulates the BCL-2 gene but not other BCL-2 family members via DOT1L-mediated H3K79me2/3. We use this information to show that a t(4;11) cell line is sensitive to a combination of ABT-199 and DOT1L inhibitors. In addition, ABT-199 synergizes with standard induction-type therapy in a xenotransplant model, advocating for the introduction of ABT-199 into therapeutic regimens for MLL-rearranged leukemias. Therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of research. Mutations in the MLL gene cause aggressive incurable leukemias. Benito et al. show that MLL leukemias are highly sensitive to BCL-2 inhibitors, especially when combined with drugs that target mutant MLL complex activity

Diabetic cardiomyopathy

Diabetic cardiomyopathy is a distinct primary disease process, independent of coronary artery disease, which leads to heart failure in diabetic patients. Epidemiological and clinical trial data have confirmed the greater incidence and prevalence of heart failure in diabetes. Novel echocardiographic and MR (magnetic resonance) techniques have enabled a more accurate means of phenotyping diabetic cardiomyopathy. Experimental models of diabetes have provided a range of novel molecular targets for this condition, but none have been substantiated in humans. Similarly, although ultrastructural pathology of the microvessels and cardiomyocytes is well described in animal models, studies in humans are small and limited to light microscopy. With regard to treatment, recent data with thiazoledinediones has generated much controversy in terms of the cardiac safety of both these and other drugs currently in use and under development. Clinical trials are urgently required to establish the efficacy of currently available agents for heart failure, as well as novel therapies in patients specifically with diabetic cardiomyopathy

Her Body Parts, His Body Parts

In this tabloid format catalogue, two Newfoundland artists are interviewed separately on their work centered on the male and female bodies. She, Golfman, addresses feminist problematics in her conversation with Stone; while he, Hanson, defends his small computerized images. Biographical notes