Generation of Functional CLL-Specific Cord Blood CTL Using CD40-Ligated CLL APC

PMCID: PMC3526610This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Ibrutinib for Relapsed / Refractory CLL: A UK and Ireland Analysis of Outcomes in 315 patients

In 2014, ibrutinib was made available for relapsed/refractory chronic lymphocytic leukaemia (CLL) patients. The UK CLL Forum collected data from UK/Ireland patients with a minimum of 1 year follow-up with pre-planned primary endpoints; the number of patients still on therapy at 1 year (Discontinuation Free Survival; DFS) and 1 year overall survival (OS). With a median 16 months follow-up, data on 315 patients demonstrated 1 year DFS of 73.7% and 1 year OS of 83.8%. Patients with better pre-treatment performance status (PS 0/1 vs 2+) had superior DFS (77.5% vs 61.3%;p14 days and had OS of 89.7%, while 26% of patients had dose reductions and 13% had temporary treatment breaks >14 days. We could not demonstrate a detrimental effect of dose reductions alone (1 year OS: 91.7%), but patients who had first year treatment breaks > 14 days, particularly permanent cessation of ibrutinib had both reduced 1 year OS (68.5%) and also a statistically significant excess mortality rate beyond one year. Although outcomes appear inferior to the RESONATE trial (1 year OS;90%: PFS;84%), this may partly reflect the inclusion of PS 2+ patients and that 17.5% of patients permanently discontinued ibrutinib due to an event other than disease progression

Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution

Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis of hematopoietic stem/progenitor cells (HSPCs) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukemia (sAML). All patients showed dominant TP53 ‘multihit’ HSPC clones at transformation, with a leukemia stem cell transcriptional signature strongly predictive of adverse outcomes in independent cohorts, across both TP53-mutant and wild-type (WT) AML. Through analysis of serial samples, antecedent TP53-heterozygous clones and in vivo perturbations, we demonstrate a hitherto unrecognized effect of chronic inflammation, which suppressed TP53 WT HSPCs while enhancing the fitness advantage of TP53-mutant cells and promoted genetic evolution. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukemia, and are of broad relevance to other cancer types

The History and Prehistory of Natural-Language Semantics

Contemporary natural-language semantics began with the assumption that the meaning of a sentence could be modeled by a single truth condition, or by an entity with a truth-condition. But with the recent explosion of dynamic semantics and pragmatics and of work on non- truth-conditional dimensions of linguistic meaning, we are now in the midst of a shift away from a truth-condition-centric view and toward the idea that a sentence’s meaning must be spelled out in terms of its various roles in conversation. This communicative turn in semantics raises historical questions: Why was truth-conditional semantics dominant in the first place, and why were the phenomena now driving the communicative turn initially ignored or misunderstood by truth-conditional semanticists? I offer a historical answer to both questions. The history of natural-language semantics—springing from the work of Donald Davidson and Richard Montague—began with a methodological toolkit that Frege, Tarski, Carnap, and others had created to better understand artificial languages. For them, the study of linguistic meaning was subservient to other explanatory goals in logic, philosophy, and the foundations of mathematics, and this subservience was reflected in the fact that they idealized away from all aspects of meaning that get in the way of a one-to-one correspondence between sentences and truth-conditions. The truth-conditional beginnings of natural- language semantics are best explained by the fact that, upon turning their attention to the empirical study of natural language, Davidson and Montague adopted the methodological toolkit assembled by Frege, Tarski, and Carnap and, along with it, their idealization away from non-truth-conditional semantic phenomena. But this pivot in explana- tory priorities toward natural language itself rendered the adoption of the truth-conditional idealization inappropriate. Lifting the truth-conditional idealization has forced semanticists to upend the conception of linguistic meaning that was originally embodied in their methodology

Development of a blood-based gene expression algorithm for assessment of obstructive coronary artery disease in non-diabetic patients

<p>Abstract</p> <p>Background</p> <p>Alterations in gene expression in peripheral blood cells have been shown to be sensitive to the presence and extent of coronary artery disease (CAD). A non-invasive blood test that could reliably assess obstructive CAD likelihood would have diagnostic utility.</p> <p>Results</p> <p>Microarray analysis of RNA samples from a 195 patient Duke CATHGEN registry case:control cohort yielded 2,438 genes with significant CAD association (p < 0.05), and identified the clinical/demographic factors with the largest effects on gene expression as age, sex, and diabetic status. RT-PCR analysis of 88 CAD classifier genes confirmed that diabetic status was the largest clinical factor affecting CAD associated gene expression changes. A second microarray cohort analysis limited to non-diabetics from the multi-center PREDICT study (198 patients; 99 case: control pairs matched for age and sex) evaluated gene expression, clinical, and cell population predictors of CAD and yielded 5,935 CAD genes (p < 0.05) with an intersection of 655 genes with the CATHGEN results. Biological pathway (gene ontology and literature) and statistical analyses (hierarchical clustering and logistic regression) were used in combination to select 113 genes for RT-PCR analysis including CAD classifiers, cell-type specific markers, and normalization genes.</p> <p>RT-PCR analysis of these 113 genes in a PREDICT cohort of 640 non-diabetic subject samples was used for algorithm development. Gene expression correlations identified clusters of CAD classifier genes which were reduced to meta-genes using LASSO. The final classifier for assessment of obstructive CAD was derived by Ridge Regression and contained sex-specific age functions and 6 meta-gene terms, comprising 23 genes. This algorithm showed a cross-validated estimated AUC = 0.77 (95% CI 0.73-0.81) in ROC analysis.</p> <p>Conclusions</p> <p>We have developed a whole blood classifier based on gene expression, age and sex for the assessment of obstructive CAD in non-diabetic patients from a combination of microarray and RT-PCR data derived from studies of patients clinically indicated for invasive angiography.</p> <p>Clinical trial registration information</p> <p>PREDICT, Personalized Risk Evaluation and Diagnosis in the Coronary Tree, <url>http://www.clinicaltrials.gov</url>, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00500617">NCT00500617</a></p

Crop Updates 2010 - Crop Specific

This session covers twenty four papers from different authors: PLENARY 1. Challenges facing western Canadian cropping over the next 10 years, Hugh J Beckie, Research Centre, Agriculture and Agri-Food Canada, Saskatoon, Saskatchewan CROP SPECIFIC Breeding 2. The challenge of breeding canola hybrids – new opportunities for WA growers, Wallace Cowling, Research Director, Canola Breeders Western Australia Pty Ltd 3. Chickpea 2009 crop variety testing of germplasm developed by DAFWA/CLIMA/ICRISAT/COGGO alliance. Khan, TN1,3, Adhikari, K1,3, Siddique, K2, Garlinge, J1, Smith, L1, Morgan, S1 and Boyd, C1 1Department of Agriculture and Food, Western Australia (DAFWA), 2Insititute of Agriculture, The University of Western Australia (UWA), 3Centre for Legumes in Mediterranean Agriculture (CLIMA), The University of Western Australia 4. PBA Pulse Breeding Australia – 2009 Field Pea Results, Ian Pritchard1, Chris Veitch1, Colin Boyd1, Stuart Morgan1, Alan Harris1 and Tony Leonforte2, 1Department of Agriculture and Food, Western Australia, 2Department of Primary Industries, Victoria 5. PBA Pulse Breeding Australia – 2009 Chickpea Results, Ian Pritchard1, Chris Veitch1, Colin Boyd1, Murray Blyth1, Shari Dougal1 and Kristy Hobson2 1Department of Agriculture and Food, Western Australia, 2Department of Primary Industries, Victoria Decision Support 6. A tool for identifying problems in wheat paddocks, Ben Curtis and Doug Sawkins, Department of Agriculture and Food 7. DAFWA Seasonal Forecast for 2010, Stephens, D, Department of Agriculture and Food, Western Australian, Climate and Modelling Group Disease 8. Enhancement of black spot resistance in field pea, Kedar Adhikari, T Khan, S Morgan and C Boyd, Department of Agriculture and Food, 9. fungicide management of yellow spot in wheat, Ciara Beard, Kith Jayasena, Kazue Tanaka and Anne Smith, Department of Agriculture and Food 10. Resistance to infection by Beet western yellows virus in four Australian canola varieties, Brenda Coutts and Roger Jones, Department of Agriculture and Food 11. Yellow spot carryover risk from stubble in wheat-on-wheat rotations, Jean Galloway, Pip Payne and Tess Humphreys, Department of Agriculture and Food 12. Fungicides for the future: Management of Barley Powdery Mildew and Leaf Rust, Kith Jayasena, Kazue Tanaka and William MacLeod, Department of Agriculture and Food 13. 2009 canola disease survey and management options for blackleg and Sclerotinia in 2010, Ravjit Khangura, WJ MacLeod, M Aberra and H Mian, Department of Agriculture and Food 14. Impact of variety and fungicide on carryover of stubble borne inoculum and yellow spot severity in continuous wheat cropping, Geoff Thomas, Pip Payne, Tess Humphreys and Anne Smith, Department of Agriculture and Food 15. Limitations to the spread of Wheat streak mosaic virus by the Wheat curl mite in WA during 2009, Dusty Severtson, Peter Mangano, Brenda Coutts, Monica Kehoe and Roger Jones, Department of Agriculture and Food 16. Viable solutions for barley powdery mildew, Madeline A. Tucker, Australian Centre for Necrotrophic Fungal Pathogens, Murdoch University Marketing 17. The importance of varietal accreditation in a post-deregulation barley marketing environment, Neil Barker, Barley Australia 18. Can Australia wheat meet requirements for a new middle east market? Robert Loughman, Larisa Cato, Department of Agriculture and Food, and Ken Quail, BRI Australia VARIETY PERFORMANCE 19. Sowing rate and time for hybrid vs open-pollinated canola, Mohammad Amjad and Mark Seymour, Department of Agriculture and Food 20. HYOLA® National Hybrid vs OP Canola Hybrid F1 vs Retained Seed Generation Trial Results and recommendations for growers, Justin Kudnig, Mark Thompson, Anton Mannes, Michael Uttley, Chris Fletcher, Andrew Etherton, Nick Joyce and Kate Light, Pacific Seeds Australia 21. HYOLA® National Hybrid vs OP Canola Sowing Rate Trial Results and plant population recommendations for Australian growers, Justin Kudnig, Mark Thompson, Anton Mannes, Michael Uttley, Andrew Etherton, Chris Fletcher, Nick Joyce and Kate Light, Pacific Seeds Australia; Peter Hamblin, Agritech Research Young, NSW, Michael Lamond, Agrisearch, York, Western Australia 22. Desi chickpea agronomy for 2010, Alan Meldrum, Pulse Australia and Wayne Parker, Department of Agriculture and Food 23. New wheat varieties – exploit the benefits and avoid the pitfalls, Steve Penny, Sarah Ellis, Brenda Shackley, Christine Zaicou, Shahajahan Miyan, Darshan Sharma and Ben Curtis, Department of Agriculture and Food 24. The influence of genetics and environment on the level of seed alkaloid in narrow-leafed lupins, Greg Shea1, Bevan Buirchell1, David Harris2 and Bob French1, 1Department of Agriculture and Food, 2ChemCentr

Immunological aspects in chronic lymphocytic leukemia (CLL) development

Chronic lymphocytic leukemia (CLL) is unique among B cell malignancies in that the malignant clones can be featured either somatically mutated or unmutated IGVH genes. CLL cells that express unmutated immunoglobulin variable domains likely underwent final development prior to their entry into the germinal center, whereas those that express mutated variable domains likely transited through the germinal center and then underwent final development. Regardless, the cellular origin of CLL remains unknown. The aim of this review is to summarize immunological aspects involved in this process and to provide insights about the complex biology and pathogenesis of this disease. We propose a mechanistic hypothesis to explain the origin of B-CLL clones into our current picture of normal B cell development. In particular, we suggest that unmutated CLL arises from normal B cells with self-reactivity for apoptotic bodies that have undergone receptor editing, CD5 expression, and anergic processes in the bone marrow. Similarly, mutated CLL would arise from cells that, while acquiring self-reactivity for autoantigens—including apoptotic bodies—in germinal centers, are also still subject to tolerization mechanisms, including receptor editing and anergy. We believe that CLL is a proliferation of B lymphocytes selected during clonal expansion through multiple encounters with (auto)antigens, despite the fact that they differ in their state of activation and maturation. Autoantigens and microbial pathogens activate BCR signaling and promote tolerogenic mechanisms such as receptor editing/revision, anergy, CD5+ expression, and somatic hypermutation in CLL B cells. The result of these tolerogenic mechanisms is the survival of CLL B cell clones with similar surface markers and homogeneous gene expression signatures. We suggest that both immunophenotypic surface markers and homogenous gene expression might represent the evidence of several attempts to re-educate self-reactive B cells

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes