Perspective: Current advances in solid-state NMR spectroscopy

In contrast to the rapid and revolutionary impact of solution-state Nuclear Magnetic Resonance (NMR) on modern chemistry, the field of solid-state NMR has matured more slowly. This reflects the major technical challenges of much reduced spectral resolution and sensitivity in solid-state as compared to solution-state spectra, as well as the relative complexity of the solid state. In this perspective, we outline the technique developments that have pushed resolution to intrinsic limits and the approaches, including ongoing major developments in the field of Dynamic Nuclear Polarisation, that have enhanced spectral sensitivity. The information on local structure and dynamics that can be obtained using these gains in sensitivity and resolution is illustrated with a diverse range of examples from large biomolecules to energy materials and pharmaceuticals and from both ordered and highly disordered materials. We discuss how parallel developments in quantum chemical calculation, particularly density functional theory, have enabled experimental data to be translated directly into information on local structure and dynamics, giving rise to the developing field of “NMR crystallography

Nanostructure of cellulose microfibrils in spruce wood

The structure of cellulose microfibrils in wood is not known in detail, despite the abundance of cellulose in woody biomass and its importance for biology, energy, and engineering. The structure of the microfibrils of spruce wood cellulose was investigated using a range of spectroscopic methods coupled to small-angle neutron and wide-angle X-ray scattering. The scattering data were consistent with 24-chain microfibrils and favored a “rectangular” model with both hydrophobic and hydrophilic surfaces exposed. Disorder in chain packing and hydrogen bonding was shown to increase outwards from the microfibril center. The extent of disorder blurred the distinction between the I alpha and I beta allomorphs. Chains at the surface were distinct in conformation, with high levels of conformational disorder at C-6, less intramolecular hydrogen bonding and more outward-directed hydrogen bonding. Axial disorder could be explained in terms of twisting of the microfibrils, with implications for their biosynthesis

European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia

From the laboratory perspective, effective management of patients with chronic myeloid leukemia (CML) requires accurate diagnosis, assessment of prognostic markers, sequential assessment of levels of residual disease and investigation of possible reasons for resistance, relapse or progression. Our scientific and clinical knowledge underpinning these requirements continues to evolve, as do laboratory methods and technologies. The European LeukemiaNet convened an expert panel to critically consider the current status of genetic laboratory approaches to help diagnose and manage CML patients. Our recommendations focus on current best practice and highlight the strengths and pitfalls of commonly used laboratory tests

Eradication of chronic myeloid leukemia stem cells: a novel mathematical model predicts no therapeutic benefit of adding G-CSF to imatinib

Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggested as a mechanism conferring insensitivity to imatinib, and exposure to the Granulocyte-Colony Stimulating Factor (G-CSF), together with imatinib, has led to a significant reduction in leukemic stem cells in vitro. In this paper, we design a novel mathematical model of stem cell quiescence to investigate the treatment response to imatinib and G-CSF. We find that the addition of G-CSF to an imatinib treatment protocol leads to observable effects only if the majority of leukemic stem cells are quiescent; otherwise it does not modulate the leukemic cell burden. The latter scenario is in agreement with clinical findings in a pilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the production of cycling leukemic stem cells. Although the pilot study did not include enough patients to draw any conclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib. Our results suggest that the additional use of G-CSF may be detrimental to patients in the clinic

Cost and quality issues in establishing hematopoietic cell transplant program in developing countries

The hematopoietic cell transplant (HCT) activity has grown significantly over the past two decades in both developing and developed countries. Many challenges arise in establishing new HCT programs in developing countries, due to scarcity of resources and manpower in expertise in HCT. While cost issues can potentially hinder establishment of new HCT programs in certain regions, the focus on quality and value should be included in the general vision of leadership before establishing an HCT program. The main challenge in most developing countries is the lack of trained/qualified personnel, enormous start-up costs for a tertiary care center, and quality maintenance. Herein, we discuss the main challenges from a cost and quality perspective which occur at initiation of a new HCT program. We give real world examples of two developing countries that have recently started new HCT programs despite significant financial constraints. We also portray recommendations from the Worldwide Network of Blood and Marrow Transplantation for levels of requirements for a new HCT program. We hope that this review will serve as a general guide for new transplant program leadership with respect to the concerns of balancing high quality with concurrently lowering costs

Time invaders:conceptualizing performative game time

This chapter characterizes framing devices and other game elements as unstable signifiers, evaluating performances according to how they generate diachronic or synchronic effects by acting on those signifiers. Videogames make use of computers’ capabilities to present a very large set of these signifiers and thus generate highly complex forms of temporal experience. Because neither diachrony (exemplified by player performance) nor synchrony (computer-coded rule structures) can complete their respective operations and always leave a differential margin, videogames can be understood as diachrono-synchronic systems.Performative multiplicities of various sizes can be analyzed in terms of how they draw together or separate performances, creating a comparative methodology for describing temporal experience in videogames. One of the key synchronic effects is the Game Over, which has a high-level effect on all performances of a game. Considered as a synchronic horizon of experience, the Game Over provides a concept capable of addressing the heterogeneous and composite set of videogame elements in terms of how players interpret unstable signifiers. This includes narrative, which can be rigorously defined in terms of its synchronizing effect on a game’s performative multiplicity

Alloreactivity: the Janus-face of hematopoietic stem cell transplantation

Differences in major and minor histocompatibility antigens between donor and recipient trigger powerful graft-versus-host reactions after allogeneic hematopoietic stem cell transplantation (HSCT). The clinical effects of alloreactivity present a Janus-face: detrimental graft-versus-host disease increases non-relapse mortality, beneficial graft-versus-malignancy may cure the recipient. The ultimate consequences on long-term outcome remain a matter of debate. We hypothesized that increasing donor-recipient antigen matching would decrease the negative effects, while preserving antitumor alloreactivity. We analyzed retrospectively a predefined cohort of 32 838 such patients and compared it to 59 692 patients with autologous HSCT as reference group. We found a significant and systematic decrease in non-relapse mortality with decreasing phenotypic and genotypic antigen disparity, paralleled by a stepwise increase in overall and relapse-free survival (Spearman correlation coefficients of cumulative excess event rates at 5 years 0.964; P<0.00; respectively 0.976; P<0.00). We observed this systematic stepwise effect in all main disease and disease-stage categories. The results suggest that detrimental effects of alloreactivity are additive with each step of mismatching; the beneficial effects remain preserved. Hence, if there is a choice, the best match should be donor of choice. The data support an intensified search for predictive genomic and environmental factors of ‘no-graft-versus-host disease’.Leukemia advance online publication, 7 April 2017; doi:10.1038/leu.2017.79

BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase

BCR-ABL1 mutations are a common, well-characterized mechanism of resistance to imatinib as first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). Less is known about mutation development during first-line treatment with dasatinib and nilotinib, despite increased use because of higher response rates compared with imatinib. Retrospective analyses were conducted to characterize mutation development in patients with newly diagnosed CML-CP treated with dasatinib (n=259) or imatinib (n=260) in DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML-CP), with 3-year minimum follow-up. Mutation screening, including patients who discontinued treatment and patients who had a clinically relevant on-treatment event (no confirmed complete cytogenetic response (cCCyR) and no major molecular response (MMR) within 12 months; fivefold increase in BCR-ABL1 with loss of MMR; loss of CCyR), yielded a small number of patients with mutations (dasatinib, n=17; imatinib, n=18). Dasatinib patients had a narrower spectrum of mutations (4 vs 12 sites for dasatinib vs imatinib), fewer phosphate-binding loop mutations (1 vs 9 mutations), fewer multiple mutations (1 vs 6 patients) and greater occurrence of T315I (11 vs 0 patients). This trial was registered at www.clinicaltrials.gov as NCT00481247.T P Hughes, G Saglio, A Quintás-Cardama, M J Mauro, D-W Kim, J H Lipton6, M B Bradley-Garelik, J Ukropec and A Hochhau