Initiation of fluid-induced fracture in a thick-walled hollow permeable sphere

The initiation of fluid-induced fracture in formations of permeable geomaterials subjected to quasi-stationary flow processes (drained response) can be strongly affected by Biot's coefficient and the size of the formation. The aim of this paper is to analyse the influence of these parameters on the initial fracture process of a thick-walled hollow permeable sphere subjected to fluid injection in the hole. Assuming that fracture patterns are distributed uniformly during the hardening stage of the fracture initiation process, the coupled fluid-solid problem is described by a nonlinear ordinary differential equation, which is solved numerically by means of finite differences combined with shooting and Newton methods. The finite difference code has also been validated in the elastic range, i.e., before initiation of fracture, against an original closed-form analytical solution of the above differential equation. The results show that the nominal strength of the sphere increases with increasing Biot's coefficient and decreases with increasing size

Novel epigenetic therapies in hematological malignancies: Current status and beyond

Over the last decade transcriptional dysregulation and altered epigenetic programs have emerged as a hallmark in the majority of hematological cancers. Several epigenetic regulators are recurrently mutated in many hematological malignancies. In addition, in those cases that lack epigenetic mutations, altered function of epigenetic regulators has been shown to play a central role in the pathobiology of many hematological neoplasms, through mechanisms that are becoming increasingly understood. This, in turn, has led to the development of small molecule inhibitors of dysregulated epigenetic pathways as novel targeted therapies for hematological malignancies. In this review, we will present the most recent advances in our understanding of the role played by dysregulated epigenetic programs in the development and maintenance of hematological neoplasms. We will describe novel therapeutics targeting altered epigenetic programs and outline their mode of action. We will then discuss their use in specific conditions, identify potential limitations and putative toxicities while also providing an update on their current clinical development. Finally, we will highlight the opportunities presented by epigenetically targeted therapies in hematological malignancies and introduce the challenges that need to be tackled by both the research and clinical communities to best translate these novel therapies into clinical practice and to improve patient outcomes.We would like to thank all the members of the Huntly laboratory and our funders including the European Research Council, MRC, Bloodwise, the Kay Kendall Leukaemia Fund, the Wellcome Trust, the Cambridge NIHR Biomedical Research Centre, and core support grants to the Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute

A comparative study of the effects of particle grading and compaction effort on the strength and stiffness of earth building materials at different humidity levels

This paper presents an investigation of the mechanical properties of three different earth building materials manufactured by compacting two soils with distinct particle size distributions under two markedly different efforts. Multiple samples of each material have been equalised either inside a climatic chamber at different humidity levels or oven-dried, before being subjected to shearing inside a triaxial cell to measure the corresponding levels of strength and stiffness. Triaxial shearing has been performed under different levels of radial stress to investigate the effect of material confinement inside thick walls. Consistent with previous research, the study has indicated that strength and stiffness increase as ambient humidity reduces and degree of saturation decreases, though the actual variation of these properties strongly depends on the dry density and clay content of the material. Most importantly, particle grading has emerged as a key material parameter, whose impact on earth building has often been overlooked. Particle grading appears to influence strength and stiffness even more than compaction effort, dry density and average particle size, which are usually quoted as the most important variables for the design of earth building materials

Earth stabilisation via carbonate precipitation by plant-derived urease for building applications

Raw (unfired) earth represents a sustainable and efficient alternative to traditional construction materials but its dissemination into building practice has been hindered by a relatively high vulnerability to water erosion. Enzyme induced carbonate precipitation (EICP) can improve the durability of earth materials without using traditional chemical binders such as cement and lime. EICP utilises the urease enzyme to catalyse the hydrolysis of urea, which produces carbonate ions that react with the calcium ions dissolved in the pore water, thus resulting in the precipitation of calcium carbonate. The calcium carbonate fills the soil voids and binds particles together, which reduces water permeability and increases material strength. The urease enzyme is a hexameric protein that is found in the tissues of many common plants. This work proposes a low-cost and simple stabilisation technology that makes use of crude urease enzyme extracted from soybeans. This technology is applied to the stabilisation of compacted earth, whose properties are then assessed via unconfined compression, moisture buffering and durability tests. The findings suggest a noticeable improvement of material strength and durability, though further investigation is necessary to increase the competitiveness of EICP stabilisation against standard techniques using cement and lime

Genetic Diversity of Pseudomonas syringae pv. actinidiae Strains from Different Geographic Regions in China

Pseudomonas syringae pv. actinidiae causes kiwifruit bacterial canker, with severe infection of the kiwifruit plant resulting in heavy economic losses. Little is known regarding the biodiversity and genetic variation of populations of P. syringae pv. actinidiae in China. A collection of 269 strains of P. syringae pv. actinidiae was identified from 300 isolates obtained from eight sampling sites in five provinces in China. The profiles of 50 strains of P. syringae pv. actinidiae and one strain of P. syringae pv. actinidifoliorum were characterized by Rep-, insertion sequences 50, and randomly amplified polymorphic DNA polymerase chain reaction (PCR). Discriminant analysis of principal coordinates, principal component analysis, and hierarchical cluster analysis were used to analyze the combined fingerprints of the different PCR assays. The results revealed that all isolates belonged to the Psa3 group, that strains of P. syringae pv. actinidiae from China have broad genetic variability that was related to source geographic region, and that Chinese strains can be readily differentiated from strains from France but are very similar to those from Italy. Multilocus sequence typing of 24 representative isolates using the concatenated sequences of five housekeeping genes (cts, gapA, gyrB, pfk, and rpoD) demonstrated that strain Jzhy2 from China formed an independent clade compared with the other biovars, which possessed the hopH1 effector gene but lacked the hopA1 effector gene. A constellation analysis based on the presence or absence of the four loci coding for phytotoxins and a cluster analysis based on the 11 effector genes showed that strains from China formed two distinct clades. All of the strains, including K3 isolated in 1997 from Jeju, Korea, lacked the cfl gene coding for coronatine. In contrast, the tox-argK gene cluster coding for phaseolotoxin was detected in K3 and in the biovar 1 strains (K3, Kw30, and Psa92), and produced a false-positive amplicon for the hopAM1-like gene in this study. To date, only one biovar (biovar 3) is represented by the strains of P. syringae pv. actinidiae from China, despite China being the center of origin for kiwifruit

The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia.

Growing evidence links abnormal epigenetic control to the development of hematological malignancies. Accordingly, inhibition of epigenetic regulators is emerging as a promising therapeutic strategy. The acetylation status of lysine residues in histone tails is one of a number of epigenetic post-translational modifications that alter DNA-templated processes, such as transcription, to facilitate malignant transformation. Although histone deacetylases are already being clinically targeted, the role of histone lysine acetyltransferases (KAT) in malignancy is less well characterized. We chose to study this question in the context of acute myeloid leukemia (AML), where, using in vitro and in vivo genetic ablation and knockdown experiments in murine models, we demonstrate a role for the epigenetic regulators CBP and p300 in the induction and maintenance of AML. Furthermore, using selective small molecule inhibitors of their lysine acetyltransferase activity, we validate CBP/p300 as therapeutic targets in vitro across a wide range of human AML subtypes. We proceed to show that growth retardation occurs through the induction of transcriptional changes that induce apoptosis and cell-cycle arrest in leukemia cells and finally demonstrate the efficacy of the KAT inhibitors in decreasing clonogenic growth of primary AML patient samples. Taken together, these data suggest that CBP/p300 are promising therapeutic targets across multiple subtypes in AML.Funding in the Huntly laboratory comes from Cancer Research UK, Leukemia Lymphoma Research, the Kay Kendal Leukemia Fund, the Leukemia lymphoma Society of America, the Wellcome Trust, The Medical Research Council and an NIHR Cambridge Biomedical Research Centre grant. Patient samples were processed in the Cambridge Blood and Stem Cell Biobank.This is the author accepted manuscript. The final version is available via NPG at http://dx.doi.org/10.1038/onc.2015.9

A randomised Phase II trial of Hydroxychloroquine and Imatinib versus Imatinib alone for patients with Chronic Myeloid Leukaemia in Major Cytogenetic Response with residual disease

In chronic-phase chronic myeloid leukaemia (CP-CML), residual BCR-ABL1+ leukaemia stem cells are responsible for disease persistence despite TKI. Based on in vitro data, CHOICES (CHlorOquine and Imatinib Combination to Eliminate Stem cells) was an international, randomised phase II trial designed to study the safety and efficacy of imatinib (IM) and hydroxychloroquine (HCQ) compared with IM alone in CP-CML patients in major cytogenetic remission with residual disease detectable by qPCR. Sixty-two patients were randomly assigned to either arm. Treatment ‘successes’ was the primary end point, defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end points were 24-month treatment ‘successes’, molecular response and progression at 12 and 24 months, comparison of IM levels, and achievement of blood HCQ levels >2000 ng/ml. At 12 months, there was no difference in ‘success’ rate (p = 0.58); MMR was achieved in 80% (IM) vs 92% (IM/HCQ) (p = 0.21). At 24 months, the ‘success’ rate was 20.8% higher with IM/HCQ (p = 0.059). No patients progressed. Seventeen serious adverse events, including four serious adverse reactions, were reported; diarrhoea occurred more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML