Class III beta-tubulin overexpression is a marker of resistance to microtubule disruptors in vitro, in vivo and in the clinic for many cancers, including breast cancer. The aims of this study were to ...develop a new model of class III beta-tubulin expression, avoiding the toxicity associated with chronic overexpression of class III beta-tubulin, and study the efficacy of a panel of clinical and pre-clinical drugs in this model.
MCF-7 (ER+ve) and MDA-MB-231 (ER-ve) were either transfected with pALTER-TUBB3 or siRNA-tubb3 and 24 h later exposed to test compounds for a further 96 h for proliferation studies. RT-PCR and immunoblotting were used to monitor the changes in class III beta-tubulin mRNA and protein expression.
The model allowed for subtle changes in class III beta-tubulin expression to be achieved, which had no direct effect on the viability of the cells. Class III beta-tubulin overexpression conferred resistance to paclitaxel and vinorelbine, whereas downregulation of class III beta-tubulin rendered cells more sensitive to these two drugs. The efficacy of the colchicine-site binding agents, 2-MeOE2, colchicine, STX140, ENMD1198 and STX243 was unaffected by the changes in class III beta-tubulin expression.
These data indicate that the effect of class III beta-tubulin overexpression may depend on where the drug's binding site is located on the tubulin. Therefore, this study highlights for the first time the potential key role of targeting the colchicine-binding site, to develop new treatment modalities for taxane-refractory breast cancer.
The bistability of cross-ply 0
n/90
n
T laminates has already been investigated, both experimentally and analytically, in much detail. Bistability occurs due to geometric non-linearity and the ...mismatch between the thermal expansion coefficients of the constituent fibre and matrix materials. In this current work a new type of bistable laminate is presented which has a symmetric lay-up. Its bistability derives from careful manipulation of the residual stresses across the width of the laminate. This is done by applying a prestress to selected fibres in 0/90/90/0
T FRP prepreg laminates prior to curing. Once cured and cooled down this prestress is released and the resulting laminate then buckles. This buckling creates two bistable bowing geometries with two edges remaining relatively flat. Analytical and finite element modelling is also carried out to better understand this buckling mechanism. Potential applications of these new bistable composites include morphing aircraft skins.
Background and purpose: Carboxylesterases (CEs) metabolize a wide range of xenobiotic substrates including heroin, cocaine, meperidine and the anticancer agent CPT‐11. In this study, we have ...purified to homogeneity human liver and intestinal CEs and compared their ability with hydrolyse heroin, cocaine and CPT‐11.
Experimental approach: The hydrolysis of heroin and cocaine by recombinant human CEs was evaluated and the kinetic parameters determined. In addition, microsomal samples prepared from these tissues were subjected to chromatographic separation, and substrate hydrolysis and amounts of different CEs were determined.
Key results: In contrast to previous reports, cocaine was not hydrolysed by the human liver CE, hCE1 (CES1), either as highly active recombinant protein or as CEs isolated from human liver or intestinal extracts. These results correlated well with computer‐assisted molecular modelling studies that suggested that hydrolysis of cocaine by hCE1 (CES1), would be unlikely to occur. However, cocaine, heroin and CPT‐11 were all substrates for the intestinal CE, hiCE (CES2), as determined using both the recombinant protein and the tissue fractions. Again, these data were in agreement with the modelling results.
Conclusions and implications: These results indicate that the human liver CE is unlikely to play a role in the metabolism of cocaine and that hydrolysis of this substrate by this class of enzymes is via the human intestinal protein hiCE (CES2). In addition, because no enzyme inhibition is observed at high cocaine concentrations, potentially this route of hydrolysis is important in individuals who overdose on this agent.
The objective of this secondary analysis was to explore differences in baseline clinical characteristics and opioid replacement therapy treatment outcomes by type (heroin, opioid analgesic OA, or ...combined heroin and OA) and route (injector or non-injector) of opioid use.
A total of 1,269 participants (32.2% female) were randomized to receive one of two study medications (methadone or buprenorphine/naloxone BUP). Of these, 731 participants completed the 24-week active medication phase. Treatment outcomes were opioid use during the final 30 days of treatment (among treatment completers) and treatment attrition.
Non-opioid substance dependence diagnoses and injecting differentiated heroin and combined users from OA users. Non-opioid substance dependence diagnoses and greater heroin use differentiated injectors from non-injectors. Further, injectors were more likely to be using at end of treatment compared with non-injectors. OA users were more likely to complete treatment compared with heroin users and combined users. Non-injectors were more likely than injectors to complete treatment. There were no interactions between type of opioid used or injection status and treatment assignment (methadone or BUP) on either opioid use or treatment attrition.
Findings indicate that substance use severity differentiates heroin users from OA users and injectors from non-injectors. Irrespective of medication, heroin use and injecting are associated with treatment attrition and opioid misuse during treatment. These results have particular clinical interest, as there is no evidence of superiority of BUP over methadone for treating OA users versus heroin users.
Composite structures exhibit many different failure mechanisms, but attempts to model composite failure frequently make a priori assumptions about the mechanism by which failure will occur. Wang et ...al. 1 conducted compressive tests on four configurations of composite specimen manufactured with out-of-plane waviness created by ply-drop defects. There were significantly different failures for each case. Detailed finite element models of these experiments were developed which include competing failure mechanisms. The model predictions correlate well with experimental results – both qualitatively (location of failure and shape of failed specimen) and quantitatively (failure load). The models are used to identify the progression of failure during the compressive tests, determine the critical failure mechanism for each configuration, and investigate the effect of cohesive parameters upon specimen strength. This modelling approach which includes multiple competing failure mechanisms can be applied to predict failure in situations where the failure mechanism is not known in advance.
Haloes gone MAD: The Halo-Finder Comparison Project Knebe, Alexander; Knollmann, Steffen R.; Muldrew, Stuart I. ...
Monthly notices of the Royal Astronomical Society,
08/2011, Letnik:
415, Številka:
3
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
We present a detailed comparison of fundamental dark matter halo properties retrieved by a substantial number of different halo finders. These codes span a wide range of techniques including ...friends‐of‐friends, spherical‐overdensity and phase‐space‐based algorithms. We further introduce a robust (and publicly available) suite of test scenarios that allow halo finder developers to compare the performance of their codes against those presented here. This set includes mock haloes containing various levels and distributions of substructure at a range of resolutions as well as a cosmological simulation of the large‐scale structure of the universe.
All the halo‐finding codes tested could successfully recover the spatial location of our mock haloes. They further returned lists of particles (potentially) belonging to the object that led to coinciding values for the maximum of the circular velocity profile and the radius where it is reached. All the finders based in configuration space struggled to recover substructure that was located close to the centre of the host halo, and the radial dependence of the mass recovered varies from finder to finder. Those finders based in phase space could resolve central substructure although they found difficulties in accurately recovering its properties. Through a resolution study we found that most of the finders could not reliably recover substructure containing fewer than 30–40 particles. However, also here the phase‐space finders excelled by resolving substructure down to 10–20 particles. By comparing the halo finders using a high‐resolution cosmological volume, we found that they agree remarkably well on fundamental properties of astrophysical significance (e.g. mass, position, velocity and peak of the rotation curve).
We further suggest to utilize the peak of the rotation curve, vmax, as a proxy for mass, given the arbitrariness in defining a proper halo edge.
Australia's lizard fauna is among the most diverse in the world. Yet for the continent's vast northern Monsoonal Tropics, recent genomic and morphological evidence indicate that current taxonomy ...significantly underestimates actual biological diversity. Apparently widespread species typically contain ancient phylogenetic divisions or confounded taxonomic boundaries. Resolving the distributions and relationships across tropical species complexes reveals higher diversity than is recognised taxonomically and may warrant substantial taxonomic changes. For conservation assessments however, we need not wait for revised taxonomy, because phylogenetically informed analyses can use the best available data to inform conservation priorities now, independent of taxonomy.
We present results of a large-scale conservation analysis based on comparative phylogeography of ten genera of lizards in two families (Gekkonidae and Scincidae) across the “Top End” of northern Australia, an ecologically and topographically diverse landscape recognised for its high biodiversity and indigenous cultural values. We combine the distributions and phylogeny of evolutionary lineages across multiple species complexes to estimate phylogenetic endemism, a measure of the extent to which evolutionary diversity is geographically concentrated. We demonstrate new methods for conservation assessment to incorporate phylogenetic diversity both within and across species, and for cases where taxonomy is uncertain or incomplete.
We identify five hotspots of endemism, some previously known such as the Arnhem Plateau but others that are newly identified such as the Wessel & English Company Islands and the Darwin-Litchfield area. We find that, weighted by range size, the 28% of the region within protected areas holds 44% of the region's sampled phylogenetic diversity.
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•Maps conservation priorities for lizards in the Top End of northern Australia using comparative phylogeography•Demonstrates new methods for conservation assessment to incorporate phylogenetic diversity both within and across species•Supports conservation assessment for cases where taxonomy is uncertain or incomplete•Identifies five hotspots of endemism including the Arnhem Plateau and the Wessel & English Company Islands•Existing National Parks and Indigenous Protected Areas capture much of the evolutionary diversity of the region's lizards•Substantial gaps remain in knowledge of the region’s lizard diversity
Our understanding of the detailed recognition and processing of clinically useful therapeutic agents has grown rapidly in recent years, and we are now able to begin to apply this knowledge to the ...rational treatment of disease. Mammalian carboxylesterases (CEs) are enzymes with broad substrate specificities that have key roles in the metabolism of a wide variety of clinical drugs, illicit narcotics and chemical nerve agents. Here, the functions, mechanism of action and structures of human CEs are reviewed, with the goal of understanding how these proteins are able to act in such a non-specific fashion, yet catalyze a remarkably specific chemical reaction. Current approaches to harness these enzymes as protein-based therapeutics for drug and chemical toxin clearance are described, as well as their uses for targeted chemotherapeutic prodrug activation. Also included is an outline of how selective CE inhibitors could be used as co-drugs to improve the efficacy of clinically approved agents.
ABSTRACT
We analyse rapid-cadence, multiwavelength photometry of AR Scorpii from three observatories, covering five observing seasons. We measure the arrival times of the system’s beat pulses and use ...them to compute an updated ephemeris. The white dwarf spin-down rate is estimated with an uncertainty of only 4 per cent. These results confirm, beyond any doubt, that the white dwarf’s spin period is increasing at the rate consistent with by that of Stiller et al. (2018). We study the evolution of the beat pulse’s colour index across the orbit. The colour of the primary pulse maxima varies significantly across the orbit, with the peaks being bluer after superior conjunction than in the first half of the orbit. Specifically, at orbital phase 0.5, the colour index of the primary pulse shows a very sharp discontinuity towards bluer indices. This supports the Potter & Buckley (2018b) synchrotron emission model where the two emitting poles differ significantly in colour. However, no corresponding jump in the colour of the secondary pulses is seen. Furthermore, our analysis reveals that the arrival times of the pulses can differ by as much as 6 s in simultaneous u and r photometry, depending on the binary orbital phase. If left uncorrected, this wavelength-dependent timing offset could lead to erroneous measurements of the spin-period derivative, particularly with heterogeneous data sets.
Gene expression profiling is increasingly being utilised as a diagnostic, prognostic and predictive tool for managing cancer patients. Single-sample scoring approach has been developed to alleviate ...instability of signature scores due to variations from sample composition. However, it is a challenge to achieve comparable signature scores across different expressional platforms.
The pre-treatment biopsies from a total of 158 patients, who have received single-agent anti-PD-1 (n = 84) or anti-PD-1 + anti-CTLA-4 therapy (n = 74), were performed using NanoString PanCancer IO360 Panel. Multiple immune-related signature scores were measured from a single-sample rank-based scoring approach, singscore. We assessed the reproducibility and the performance in reporting immune profile of singscore based on NanoString assay in advance melanoma. To conduct cross-platform analyses, singscores between the immune profiles of NanoString assay and the previous orthogonal whole transcriptome sequencing (WTS) data were compared through linear regression and cross-platform prediction.
singscore-derived signature scores reported significantly high scores in responders in multiple PD-1, MHC-1-, CD8 T-cell-, antigen presentation-, cytokine- and chemokine-related signatures. We found that singscore provided stable and reproducible signature scores among the repeats in different batches and cross-sample normalisations. The cross-platform comparisons confirmed that singscores derived via NanoString and WTS were comparable. When singscore of WTS generated by the overlapping genes to the NanoString gene set, the signatures generated highly correlated cross-platform scores (Spearman correlation interquartile range (IQR) 0.88, 0.92 and r
IQR 0.77, 0.81) and better prediction on cross-platform response (AUC = 86.3%). The model suggested that Tumour Inflammation Signature (TIS) and Personalised Immunotherapy Platform (PIP) PD-1 are informative signatures for predicting immunotherapy-response outcomes in advanced melanoma patients treated with anti-PD-1-based therapies.
Overall, the outcome of this study confirms that singscore based on NanoString data is a feasible approach to produce reliable signature scores for determining patients' immune profiles and the potential clinical utility in biomarker implementation, as well as to conduct cross-platform comparisons, such as WTS.
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