B and T cell prolymphocytic leukaemia Cross, M.; Dearden, C.
Best practice & research. Clinical haematology,
September 2019, 2019-09-00, 20190901, Letnik:
32, Številka:
3
Journal Article
Recenzirano
Prolymphocytic leukaemias B-PLL and T-PLL are rare disorders, typically with an aggressive clinical course and poor prognosis. Combining morphology, immunophenotyping, cytogenetic and molecular ...diagnostics reliably separates B-PLL and T-PLL from one another and other disorders. In T-PLL discovery of frequent mutations in the JAK-STAT pathway have increased understanding of disease pathogenesis. Alemtuzumab (anti-CD52) produces excellent response rates but long-term remissions are only achieved in a minority following consolidation with allogeneic stem cell transplant. Molecular abnormalities in B-PLL are less understood. Disruption of TP53 is a key finding, conveying chemotherapy resistance requiring novel therapies such as B-cell receptor inhibitors (BCRi). Both conditions require improved pathobiological knowledge to identify new treatment targets and guide therapy with novel pathway inhibitors.
Summary Background Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this ...treatment combination provided greater survival benefit than did chlorambucil or fludarabine. Methods 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. Findings There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38% vs 15%, respectively; overall response rate 94% vs 80%, respectively; p<0·0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0·006 and 0·04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0·00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (VH ) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. Interpretation Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.
Abstract Numerical simulations are performed with the Weather Research and Forecasting Model to elucidate the diabatic effects of ice phase microphysical processes on the dynamics of two slow-moving ...summer cyclones that affected the United Kingdom during the summer of 2012. The first case is representative of a typical midlatitude storm for the time of year, while the second case is unusually deep. Sensitivity tests are performed with 5-km horizontal grid spacing and at lead times between 1 and 2 days using three different microphysics schemes, one of which is a new scheme whose development was informed by the latest in situ observations of midlatitude weather systems. The effects of latent heating and cooling associated with deposition growth, sublimation, and melting of ice are assessed in terms of the impact on both the synoptic scale and the frontal scale. The results show that, of these diabatic processes, deposition growth was the most important in both cases, affecting the depth and position of each of the low pressure systems and influencing the spatial distribution of the frontal precipitation. Cooling associated with sublimation and melting also played a role in determining the cyclone depth, but mainly in the more intense cyclone case. The effects of ice crystal habit and secondary ice production are also explored in the simulations, based on insight from in situ observations. However in these two cases, the ability to predict changes in crystal habit did not significantly impact the storm evolution, and the authors found no obvious need to parameterize secondary ice crystal production at the model resolutions considered.
Secondary ice production (SIP) commonly occurs in coastal Antarctic stratocumulus, affecting their ice number concentrations (Nice) and radiative properties. However, SIP is poorly understood and ...crudely parametrized in models. By evaluating how well SIP is captured in a cloud‐resolving model, with a high‐resolution nest within a parent domain, we test how an improved comparison with aircraft observations affects the modeled cloud radiative properties. Under the assumption that primary ice is suitably represented by the model, we must enhance SIP by up to an order of magnitude to simulate observed Nice. Over the nest, a surface warming trend accompanied the SIP increase; however, this trend was not captured by the parent domain over the same region. Our results suggest that the radiative properties of microphysical features resolved in high‐resolution nested domains may not be captured by coarser domains, with implications for large‐scale radiative balance studies over the Antarctic continent.
Plain Language Summary
Climate models do not always represent clouds well—particularly in Antarctica—because we do not fully understand them on a small scale. Clouds can affect the temperature of the surface by reflecting energy from the Sun or trapping in heat from below; therefore, they play a crucial role in Antarctica, where warming surfaces are affecting how the ice shelves are melting. We need a variety of measurements of Antarctic clouds to understand them, including how many droplets or ice crystals they contain. Using measurements from the “Microphysics of Antarctic Clouds” project, we found evidence that, at certain temperatures, significantly more ice particles can be rapidly produced when fragile ice crystals or freezing droplets break up. We use these measurements to improve how cloud ice crystals are simulated in a weather model and consider implications for the frozen surface as a result of these changes. We found better agreement with our measurements by making the ice crystals multiply more efficiently in the model. As a result, less cloud cover was simulated and more energy from the Sun reached the surface, suggesting that the Antarctic surface may be subject to more warming than we originally thought.
Key Points
Increasing modeled secondary ice production (SIP) by 10 times improves agreement with ice number concentration observations in Antarctica
Enhanced SIP reduces cloud fraction and increases amount of shortwave radiation reaching the surface over a high‐resolution nested domain
SIP‐induced changes in cloud radiative forcing over the high‐resolution nest are not captured by the coarse parent domain
Whither QSAR? Dearden, John C
Pharmaceutical Sciences,
06/2017, Letnik:
23, Številka:
2
Journal Article
Odprti dostop
A good example is the correlation of the anti-inflammatory potency of a series of ringsubstituted aspirin derivatives in the rat:1 (ProQuest: ... denotes formula omitted.) In equation 1, ED50 = dose ...required to reduce paw inflammation by 50%, P = octanol-water partition coefficient, n = number of compounds used to develop the QSAR, r2=coefficient of determination, and s = standard error of the model. The earliest quantitative property prediction that I could find is that of Döbereiner, who in 1816 accurately predicted the specific weight of strontium sulphate by interpolation (read-across, in modern parlance) from those of calcium and barium sulphates.4 Even more amazing, in a way, is the insight shown by the Roman poet and philosopher Titus Lucretius Carus (ca. 99-55 B.C.), who in his De Rerum Natura5 wrote: ...Ф = fC. A recent much-cited paper11 covers many recent QSAR advances, but also, importantly, looks back; its title includes the phrase "Where have you been?" In our quest for advancement, we should not forget the sound advice given in Occam's Razor: "Pluralitas non est ponenda sine necessitate"; there are numerous English interpretations, of which one of the best in my view is: "The simplest explanation for some phenomenon is...
In silico prediction of drug toxicity Dearden, John C
Journal of computer-aided molecular design,
02/2003, Letnik:
17, Številka:
2-4
Journal Article
Recenzirano
It is essential, in order to minimise expensive drug failures due to toxicity being found in late development or even in clinical trials, to determine potential toxicity problems as early as ...possible. In view of the large libraries of compounds now being handled by combinatorial chemistry and high-throughput screening, identification of putative toxicity is advisable even before synthesis. Thus the use of predictive toxicology is called for. A number of in silico approaches to toxicity prediction are discussed. Quantitative structure-activity relationships (QSARs), relating mostly to specific chemical classes, have long been used for this purpose, and exist for a wide range of toxicity endpoints. However, QSARs also exist for the prediction of toxicity of very diverse libraries, although often such QSARs are of the classification type; that is, they predict simply whether or not a compound is toxic, and do not give an indication of the level of toxicity. Examples are given of all of these. A number of expert systems are available for toxicity prediction, most of them covering a range of toxicity endpoints. Those discussed include TOPKAT, CASE, DEREK, HazardExpert, OncoLogic and COMPACT. Comparative tests of the ability of these systems to predict carcinogenicity show that improvement is still needed. The consensus approach is recommended, whereby the results from several prediction systems are pooled.
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•The conductivity of PEDOT:PSS electrodes was improved using dimethyl sulfoxide.•DMSO was added to the PEDOT:PSS solution or a PEDOT:PSS film was immersed in DMSO.•Large amount of PSS ...were removed from the surface of the immersed electrode.•Devices with immersed PEDOT:PSS electrodes out-performed the other DMSO treatment.•Demonstrates the potential of PEDOT:PSS electrodes as an alternative to ITO.
Indium tin oxide (ITO)-free organic photovoltaic (OPV) devices were fabricated using highly conductive poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) as the transparent conductive electrode (TCE). The intrinsic conductivity of the PEDOT:PSS films was improved by two different dimethyl sulfoxide (DMSO) treatments – (i) DMSO was added directly to the PEDOT:PSS solution (PEDOT:PSSADD) and (ii) a pre-formed PEDOT:PSS film was immersed in DMSO (PEDOT:PSSIMM). X-ray photoelectron spectroscopy (XPS) and conductive atomic force microscopy (CAFM) studies showed a large amount of PSS was removed from the PEDOT:PSSIMM electrode surface. OPV devices based on a poly(3-hexylthiophene):6,6-phenyl-C61-butyric acid methyl ester (P3HT:PCBM) bulk hetrojunction showed that the PEDOT:PSSIMM electrode out-performed the PEDOT:PSSADD electrode, primarily due to an increase in short circuit current density from 6.62mAcm−2 to 7.15mAcm−2. The results highlight the importance of optimising the treatment of PEDOT:PSS electrodes and demonstrate their potential as an alternative TCE for rapid processing and low-cost OPV and other organic electronic devices.
For registration of a chemical, European Union REACH legislation requires information on the relevant physico-chemical properties of the chemical. Predicted property values can be used when the ...predictions can be shown to be valid and adequate. The relevant physico-chemical properties that are amenable to prediction are: melting/freezing point, boiling point, relative density, vapour pressure, surface tension, water solubility, n-octanol-water partition coefficient, flash point, flammability, explosive properties, self-ignition temperature, adsorption/desorption, dissociation constant, viscosity, and air-water partition coefficient (Henry's law constant). Published quantitative structure-property relationship (QSPR) methods for all of these properties are discussed, together with relevant property prediction software, as an aid for those wishing to use predicted property values in submissions to the European Chemicals Agency (ECHA).
The development of QSAR models useful for the prediction of fish bioconcentration factor (BCF) for a wide range of different chemical classes is crucial for the assessment and prioritisation of ...potentially persistent bioaccumulative and toxic substances.
In this study we present QSAR models for BCF developed on a wide range of chemical structural classes of environmental and toxicological interest (such as dyes and various chlorinated and brominated compounds). The aim is to provide valid QSAR models, statistically validated for predictivity, for the prediction of BCF in general, but also for problematical chemical classes such as highly hydrophobic chemicals. Several descriptors, calculated by different commercially available software packages, have been employed in order to take into account relevant information provided by physicochemical properties (octanol/water partition coefficient and water solubility) and molecular features (structural and quantum-chemical molecular descriptors). The best descriptor subsets for the models were selected using the Genetic Algorithm-Variable Subset Selection strategy (GA-VSS) and calculations were performed by ordinary least squares regression. Starting from a data set of 640 compounds (log
K
ow range from −2.34 to 12.66), we developed linear QSARs, firstly for a data set of 620 compounds (log
K
ow range from −2.34 to 10.35) and secondly specifically for 87 highly hydrophobic chemicals (log
K
ow range from 6.00 to 10.35). All these models have been statistically validated (both internally by cross-validation and bootstrap and externally, by “a priori” splitting of available data by Kohonen Map-ANN in training and prediction sets) and their structural chemical domain has been verified by the leverage approach.
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