Summary
The Medical Research Council Acute Myeloid Leukaemia 12 (MRC AML12) trial (children) addressed the optimal anthracenedione/anthracycline in induction and the optimal number of courses of ...consolidation chemotherapy. 504 children (<16 years) with AML were randomized between mitoxantrone/cytarabine/etoposide or daunorubicin/cytarabine/etoposide as induction chemotherapy and 270 entered a second randomization between a total of four or five courses of treatment. Ten‐year event‐free (EFS) and overall survival (OS) was 54% and 63% respectively; the relapse rate was 35%. There was no difference in complete remission rate between the induction regimens, but there was a benefit for mitoxantrone with regard to relapse rate 32% vs. 39%; Hazard ratio (HR) 0·73; 95% confidence interval (CI) 0·54, 1·00 and disease‐free survival (DFS; 63% vs. 55%; HR 0·72; 95% CI 0·54, 0·96). However, this did not translate into a better EFS or OS (HR 0·84; 95% CI 0·63, 1·12). Results of the second randomization did not show a survival benefit for a fifth course of treatment (HR 1·01; 95% CI 0·63, 1·62), suggesting a ceiling of benefit for conventional chemotherapy and demonstrating the need for new agents. EFS was superior compared to the preceding trial AML10, partly due to fewer deaths in remission, highlighting the importance of supportive care.
Most studies of the role of biological entities as atmospheric ice-nucleating particles have focused on relatively rare supermicron particles such as bacterial cells, fungal spores and pollen grains. ...However, it is not clear that there are sufficient numbers of these particles in the atmosphere to strongly influence clouds. Here we show that the ice-nucleating activity of a fungus from the ubiquitous genus Fusarium is related to the presence of nanometre-scale particles which are far more numerous, and therefore potentially far more important for cloud glaciation than whole intact spores or hyphae. In addition, we quantify the ice-nucleating activity of nano-ice nucleating particles (nano-INPs) washed off pollen and also show that nano-INPs are present in a soil sample. Based on these results, we suggest that there is a reservoir of biological nano-INPs present in the environment which may, for example, become aerosolised in association with fertile soil dust particles.
•Biological amendments include biostimulants, organic amendments and inoculants.•Some biological amendments may have potential cumulative effects.•Modes of action of biological amendments in the ...field are not always understood.•Scientific evidence of field-scale benefits of biological amendments is limited.•On-farm participatory research has potential to provide valuable knowledge.
There is increasing interest in use of ‘alternative’ soil amendments in agriculture, but the wide range of resources and products available differ greatly in their potential to overcome soil constraints and improve nutrient use efficiency. The three main types of biological amendments can be categorised as biostimulants, organic amendments and microbial inoculants. Many have potential to influence biological, chemical and physical conditions of soil, but most are not well researched or easily used in agriculture. The main exception is legume inoculants, which are very well researched and contribute enormously to agricultural productivity when legumes are incorporated into farming systems. Biostimulants include amino acids, chitosan, seaweed extracts and humic substances. Organic amendments include manures, composts, compost derivatives and biochars. Microbial inoculants include specific bacterial inoculants for legumes, and less specialised rhizosphere bacteria, arbuscular mycorrhizal fungi, ectomycorrhizal fungi and a range of disease suppressing microorganisms. Some biological amendments applied to soil may be more effective when used in combinations rather than singly. Furthermore, those used over longer periods may have potential for cumulative effects not captured when used over shorter timeframes. Such differences in effectiveness would occur primarily where benefits involve microbial interactions with chemical and physical soil processes leading to slow transformations within the soil matrix that influence soil fertility and soil health. Similarly, addition of manures and composts may require several years for any quantifiable increase in soil organic C. Although considerable knowledge of the modes of action of many biological amendments is available, their performance under field conditions is usually less well understood. The wide variety of natural and manufactured products available in most cases precludes adequate peer-reviewed research to support claims about their effectiveness. This can lead to proliferation of unsubstantiated assertions of efficacy. This review highlights the lack of field-scale evidence of benefits for many biological amendments with potential to be used in agriculture. We propose complementary approaches of (i) laboratory- or glasshouse-scale research to understand modes of action, and (ii) targeted field-scale participatory research involving groups of farmers using on-farm trials as a forward pathway. Use of biological amendments to overcome soil constraints is expected to expand with intensification of agriculture and as a result of climate change. Therefore, information that enables farmers to discriminate among products that have different levels of effectiveness is necessary, and on-farm participatory research should contribute to addressing this need.
Karyotype is an independent indicator of prognosis in acute myeloid leukemia (AML) that is widely applied to risk-adapted therapy. Because AML is rare in children, the true prognostic significance of ...individual chromosomal abnormalities in this age group remains unclear.
This cytogenetic study of 729 childhood patients classified them into 22 subgroups and evaluated their incidence and risk.
Rearrangements of 11q23 were the most frequent abnormality found in approximately 16% of patients, with 50% of these in infants. The outcome for all patients with 11q23 abnormalities was intermediate; no difference was observed for those with t(9;11)(p21-22;q23). The core binding factor leukemias with the translocations t(8;21)(q22;q22) and inv(16)(p13q22) occurred at incidences of 14% and 7%, respectively, predominantly in older children, and their prognosis was favorable. An adverse outcome was observed in patients with monosomy 7, abnormalities of 5q, and t(6;9)(p23;q34). Abnormalities of 3q and complex karyotypes, in the absence of favorable-risk features, have been associated with an adverse outcome in adults, but the results were not significant in this childhood series. However, the presence of 12p abnormalities predicted a poor outcome.
Because the spectrum of chromosomal changes and their risk association seem to differ between children and adults with AML, biologic differences are emerging, which will contribute to the redefinition of risk stratification for different age groups in the future.
We examine the diurnal cycle of marine cloud feedback using high frequency outputs in CFMIP-2 idealised uniform +4 K SST perturbation experiments from seven CMIP5 models. Most of the inter-model ...spread in the diurnal mean marine shortwave cloud feedback can be explained by low cloud responses, although these do not explain the model responses at the neutral/weakly negative end of the feedback range, where changes in mid and high level cloud properties are more important. All of the models show reductions in marine low cloud fraction in the warmer climate, and these are in almost all cases largest in the mornings when more cloud is present in the control simulations. This results in shortwave cloud feedbacks being slightly stronger and having the largest inter-model spread at this time of day. The diurnal amplitudes of the responses of marine cloud properties to the warming climate are however small compared to the inter-model differences in their diurnally meaned responses. This indicates that the diurnal cycle of cloud feedback is not strongly relevant to understanding inter-model spread in overall cloud feedback and climate sensitivity. A number of unusual behaviours in individual models are highlighted for future investigation.
The impact of parametrized convection on cloud feedback Webb, Mark J.; Lock, Adrian P.; Bretherton, Christopher S. ...
Philosophical transactions of the Royal Society of London. Series A: Mathematical, physical, and engineering sciences,
11/2015, Letnik:
373, Številka:
2054
Journal Article
Recenzirano
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We investigate the sensitivity of cloud feedbacks to the use of convective parametrizations by repeating the CMIP5/CFMIP-2 AMIP/AMIP + 4K uniform sea surface temperature perturbation experiments with ...10 climate models which have had their convective parametrizations turned off. Previous studies have suggested that differences between parametrized convection schemes are a leading source of inter-model spread in cloud feedbacks. We find however that 'ConvOff' models with convection switched off have a similar overall range of cloud feedbacks compared with the standard configurations. Furthermore, applying a simple bias correction method to allow for differences in present-day global cloud radiative effects substantially reduces the differences between the cloud feedbacks with and without parametrized convection in the individual models. We conclude that, while parametrized convection influences the strength of the cloud feedbacks substantially in some models, other processes must also contribute substantially to the overall inter-model spread. The positive shortwave cloud feedbacks seen in the models in subtropical regimes associated with shallow clouds are still present in the ConvOff experiments. Inter-model spread in shortwave cloud feedback increases slightly in regimes associated with trade cumulus in the ConvOff experiments but is quite similar in the most stable subtropical regimes associated with stratocumulus clouds. Inter-model spread in longwave cloud feedbacks in strongly precipitating regions of the tropics is substantially reduced in the ConvOff experiments however, indicating a considerable local contribution from differences in the details of convective parametrizations. In both standard and ConvOff experiments, models with less mid-level cloud and less moist static energy near the top of the boundary layer tend to have more positive tropical cloud feedbacks. The role of non-convective processes in contributing to inter-model spread in cloud feedback is discussed.
Between 1988 and 2002, 758 children with acute myeloid leukaemia (AML) were treated on Medical Research Council (MRC) AML 10 and AML 12. MRC AML 10 tested the role of bone marrow transplantation ...following four blocks of intensive chemotherapy and found that while both allogeneic bone marrow transplant (allo-BMT) and autologous bone marrow transplant (A-BMT) significantly reduced the relapse risk (RR), this did not translate into a significant improvement in overall survival (OS). A risk group stratification based on cytogenetics and response to the first course of chemotherapy derived from MRC AML 10 was used to deliver risk-directed therapy in MRC AML 12. Allo-BMT was limited to standard and poor risk patients and A-BMT was not employed. Instead, the benefit of an additional block of treatment was tested by randomising children to receive either four or five blocks of treatment in total. While the results of MRC AML 12 remain immature, there appears to be no survival advantage for a fifth course of treatment. The 5 year OS, disease-free survival (DFS), event-free survival (EFS) and RR in MRC AML 12 are 66, 61, 56 and 35%, respectively; at present superior to MRC AML 10, which had a 5-year OS, DFS, EFS and RR of 58, 53, 49 and 42%, respectively. MRC AML trials employ a short course of triple intrathecal chemotherapy alone for CNS-directed treatment and CNS relapse is uncommon. Improvements in supportive care have contributed to improved outcomes and the number of deaths in remission fell between trials. Anthracycline-related cardiotoxicity remains a concern and the current MRC AML 15 trial tests the feasibility of reducing anthracycline dosage without compromising outcome by comparing standard MRC anthracycline-based consolidation with high-dose ara-C. MRC studies suggest that the role of allo-BMT is limited in 1st CR and that there may be a ceiling of benefit from current or conventional chemotherapy.
There is considerable evidence that the potent vasoconstrictor endothelin‐1 (ET‐1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of ...the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ETA receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH). In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including resistant hypertension, chronic kidney disease, connective tissue disease and sub‐arachnoid haemorrhage are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies. Although ET‐converting enzyme inhibitors may represent one such alternative, there have been relatively few suitable compounds developed, and consequently, clinical experience with these agents remains extremely limited. Recent advances, together with an increased understanding of the biology of the ET system provided by improved experimental tools (including cell‐specific transgenic deletion of ET receptors), should allow further targeting of clinical trials to diseases in which ET is involved and allow the therapeutic potential for targeting the ET system in cardiovascular disease to be fully realized.
British Journal of Pharmacology (2008) 153, 1105–1119; doi:10.1038/sj.bjp.0707516; published online 29 October 2007
Anthrax lethal toxin, produced by the bacterium Bacillus anthracis, is the major cause of death in animals infected with anthrax. One component of this toxin, lethal factor (LF), is suspected to be a ...metalloprotease, but no physiological substrates have been identified. Here it is shown that LF is a protease that cleaves the amino terminus of mitogen-activated protein kinase kinases 1 and 2 (MAPKK1 and MAPKK2) and that this cleavage inactivates MAPKK1 and inhibits the MAPK signal transduction pathway. The identification of a cleavage site for LF may facilitate the development of LF inhibitors.
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