Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells

Chronic myeloid leukaemia (CML) is maintained by a rare population of tyrosine kinase inhibitor (TKI)-insensitive malignant stem cells. Our long-term aim is to find a BcrAbl-independent drug that can be combined with a TKI to improve overall disease response in chronic-phase CML. Omacetaxine mepesuccinate, a first in class cetaxine, has been evaluated by clinical trials in TKI-insensitive/resistant CML. Omacetaxine inhibits synthesis of anti-apoptotic proteins of the Bcl-2 family, including (myeloid cell leukaemia) Mcl-1, leading to cell death. Omacetaxine effectively induced apoptosis in primary CML stem cells (CD34<sup>+</sup>38<sup>lo</sup>) by downregulation of Mcl-1 protein. In contrast to our previous findings with TKIs, omacetaxine did not accumulate undivided cells <i>in vitro</i>. Furthermore, the functionality of surviving stem cells following omacetaxine exposure was significantly reduced in a dose-dependant manner, as determined by colony forming cell and the more stringent long-term culture initiating cell colony assays. This stem cell-directed activity was not limited to CML stem cells as both normal and non-CML CD34<sup>+</sup> cells were sensitive to inhibition. Thus, although omacetaxine is not leukaemia stem cell specific, its ability to induce apoptosis of leukaemic stem cells distinguishes it from TKIs and creates the potential for a curative strategy for persistent disease

Managing peatland vegetation for drinking water treatment

Peatland ecosystem services include drinking water provision, flood mitigation, habitat provision and carbon sequestration. Dissolved organic carbon (DOC) removal is a key treatment process for the supply of potable water downstream from peat-dominated catchments. A transition from peat-forming Sphagnum moss to vascular plants has been observed in peatlands degraded by (a) land management, (b) atmospheric deposition and (c) climate change. Here within we show that the presence of vascular plants with higher annual above-ground biomass production leads to a seasonal addition of labile plant material into the peatland ecosystem as litter recalcitrance is lower. The net effect will be a smaller litter carbon pool due to higher rates of decomposition, and a greater seasonal pattern of DOC flux. Conventional water treatment involving coagulation-flocculation-sedimentation may be impeded by vascular plant-derived DOC. It has been shown that vascular plant-derived DOC is more difficult to remove via these methods than DOC derived from Sphagnum, whilst also being less susceptible to microbial mineralisation before reaching the treatment works. These results provide evidence that practices aimed at re-establishing Sphagnum moss on degraded peatlands could reduce costs and improve efficacy at water treatment works, offering an alternative to ‘end-of-pipe’ solutions through management of ecosystem service provision

Is there a cloud in the silver lining for imatinib?

Imatinib mesylate (Gleevec® or Glivec®), a small molecule tyrosine kinase inhibitor for the treatment of chronic myeloid leukaemia, has been said to herald the dawn of a new er-a of rationally designed, molecularly targeted oncotherapy. Lurking on the same new horizon, however, is the age-old spectre of drug resistance. This review sets the intoxicating clinical perspective against the more sobering laboratory evidence of such divergent mechanisms of imatinib resistance as gene amplification and stem cell quiescence. Polychemotherapy has already been considered to combat resistance, but a more innovative, as yet unformulated, approach may be advocated

In vivo isolated kidney perfusion with tumour necrosis factor α (TNF-α) in tumour-bearing rats

Isolated perfusion of the extremities with high-dose tumour necrosis factor α (TNF-α) plus melphalan leads to dramatic tumour response in patients with irresectable soft tissue sarcoma or multiple melanoma in transit metastases. We developed in vivo isolated organ perfusion models to determine whether similar tumour responses in solid organ tumours can be obtained with this regimen. Here, we describe the technique of isolated kidney perfusion. We studied the feasibility of a perfusion with TNF-α and assessed its anti-tumour effects in tumour models differing in tumour vasculature. The maximal tolerated dose (MTD) proved to be only 1 μg TNF-α. Higher doses appeared to induce renal failure and a secondary cytokine release with fatal respiratory and septic shock-like symptoms. In vitro, the combination of TNF-α and melphalan did not result in a synergistic growth-inhibiting effect on CC 531 colon adenocarcinoma cells, whereas an additive effect was observed on osteosarcoma ROS-1 cells. In vivo isolated kidney perfusion, with TNF-α alone or in combination with melphalan, did not result in a significant anti-tumour response in either tumour model in a subrenal capsule assay. We conclude that, because of the susceptibility of the kidney to perfusion with TNF-α, the minimal threshold concentration of TNF-α to exert its anti-tumour effects was not reached. The applicability of TNF-α in isolated kidney perfusion for human tumours seems, therefore, questionable. © 1999 Cancer Research Campaig

Hierarchical Models in the Brain

This paper describes a general model that subsumes many parametric models for continuous data. The model comprises hidden layers of state-space or dynamic causal models, arranged so that the output of one provides input to another. The ensuing hierarchy furnishes a model for many types of data, of arbitrary complexity. Special cases range from the general linear model for static data to generalised convolution models, with system noise, for nonlinear time-series analysis. Crucially, all of these models can be inverted using exactly the same scheme, namely, dynamic expectation maximization. This means that a single model and optimisation scheme can be used to invert a wide range of models. We present the model and a brief review of its inversion to disclose the relationships among, apparently, diverse generative models of empirical data. We then show that this inversion can be formulated as a simple neural network and may provide a useful metaphor for inference and learning in the brain

Phosphorus dynamics in a tropical forest soil restored after strip mining

Background and aims We hypothesized that successful early ecosystem and soil development in these P-deficient soil materials will initially depend on effective re-establishment of P storage and cycling through organic matter. This hypothesis was tested in a 26-year chronosequence of seven lightly fertilized, oxidic soil materials restored to eucalypt forest communities after bauxite mining. Methods Total P (Pt) status, Hedley P fractions and partial chemical speciation (NaOH-EDTA extraction and analysed using solution 31P NMR spectroscopy) were determined in the restored soils. Results Concentrations of Pt and most Hedley fractions changed with restoration period, declined with depth and were strongly positively correlated with C and N concentrations. Biological P dominated the Labile and Intermediate P fractions while Long-term P was dominantly inorganic. Organic P concentrations in NaOH-EDTA extracts and their chemical natures were similar in restored and unburned native forest sites. Phosphomonoesters were the dominant class of organic P. Conclusions Surprisingly rapid P accretion and fractional changes occurred over 26 years, largely in the surface soils and closely associated with organic matter status. Alkaline hydrolysis products of phosphodiesters and pyrophosphate indicated the importance of microbial P cycling. The important consequences for long-term ecosystem development and biological diversity require further study

Robot Learning with Task-Parameterized Generative Models

Task-parameterized models provide a representation of movement/behavior that can adapt to a set of task parameters describing the current situation encountered by the robot, such as location of objects or landmarks in its workspace. This paper gives an overview of the task-parameterized Gaussian mixture model (TP-GMM) introduced in previous publications, and introduces a number of extensions and ongoing challenges required to move the approach toward unconstrained environments. In particular, it discusses its generalization capability and the handling of movements with a high number of degrees of freedom. It then shows that the method is not restricted to movements in task space, but that it can also be exploited to handle constraints in joint space, including priority constraints

Stable Genetic Effects on Symptoms of Alcohol Abuse and Dependence from Adolescence into Early Adulthood

Relatively little is known about how genetic influences on alcohol abuse and dependence (AAD) change with age. We examined the change in influence of genetic and environmental factors which explain symptoms of AAD from adolescence into early adulthood. Symptoms of AAD were assessed using the four AAD screening questions of the CAGE inventory. Data were obtained up to six times by self-report questionnaires for 8,398 twins from the Netherlands Twin Register aged between 15 and 32 years. Longitudinal genetic simplex modeling was performed with Mx. Results showed that shared environmental influences were present for age 15–17 (57%) and age 18–20 (18%). Unique environmental influences gained importance over time, contributing 15% of the variance at age 15–17 and 48% at age 30–32. At younger ages, unique environmental influences were largely age-specific, while at later ages, age-specific influences became less important. Genetic influences on AAD symptoms over age could be accounted for by one factor, with the relative influence of this factor differing across ages. Genetic influences increased from 28% at age 15–17 to 58% at age 21–23 and remained high in magnitude thereafter. These results are in line with a developmentally stable hypothesis that predicts that a single set of genetic risk factors acts on symptoms of AAD from adolescence into young adulthood

Molecular dynamics simulation of humic substances

© 2014, Orsi. Humic substances (HS) are complex mixtures of natural organic material which are found almost everywhere in the environment, and particularly in soils, sediments, and natural water. HS play key roles in many processes of paramount importance, such as plant growth, carbon storage, and the fate of contaminants in the environment. While most of the research on HS has been traditionally carried out by conventional experimental approaches, over the past 20 years complementary investigations have emerged from the application of computer modeling and simulation techniques. This paper reviews the literature regarding computational studies of HS, with a specific focus on molecular dynamics simulations. Significant achievements, outstanding issues, and future prospects are summarized and discussed

Volcanic impacts on the Holocene vegetation history of Britain and Ireland? A review and meta-analysis of the pollen evidence

Volcanic ash layers show that the products of Icelandic volcanism reached Britain and Ireland many times during the Holocene. Historical records suggest that at least one eruption, that of Laki in a.d. 1783, was associated with impacts on vegetation. These results raise the question: did Icelandic volcanism affect the Holocene vegetation history of Britain and Ireland? Several studies have used pollen data to address this issue but no clear consensus has been reached. We re-analyse the palynological data using constrained ordination with various representations of potential volcanic impacts. We find that the palynological evidence for volcanic impacts on vegetation is weak but suggest that this is a case of absence of evidence and is not necessarily evidence of absence of impact. To increase the chances of identifying volcanic impacts, future studies need to maximise temporal resolution, replicate results, and investigate a greater number of tephras in a broader range of locations, including more studies from lake sediments