352 research outputs found
AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL
Chronic myelogenous leukaemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) are caused by the BCR-ABL oncogene. Imatinib inhibits the tyrosine kinase activity of the BCR-ABL protein and is an effective, frontline therapy for chronic-phase CML. However, accelerated or blast-crisis phase CML patients and Ph+ ALL patients often relapse due to drug resistance resulting from the emergence of imatinib-resistant point mutations within the BCR-ABL tyrosine kinase domain. This has stimulated the development of new kinase inhibitors that are able to over-ride resistance to imatinib. The novel, selective BCR-ABL inhibitor, AMN107, was designed to fit into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib. In addition to being more potent than imatinib (IC50<30 nM) against wild-type BCR-ABL, AMN107 is also significantly active against 32/33 imatinib-resistant BCR-ABL mutants. In preclinical studies, AMN107 demonstrated activity in vitro and in vivo against wild-type and imatinib-resistant BCR-ABL-expressing cells. In phase I/II clinical trials, AMN107 has produced haematological and cytogenetic responses in CML patients, who either did not initially respond to imatinib or developed imatinib resistance. Dasatinib (BMS-354825), which inhibits Abl and Src family kinases, is another promising new clinical candidate for CML that has shown good efficacy in CML patients. In this review, the early characterisation and development of AMN107 is discussed, as is the current status of AMN107 in clinical trials for imatinib-resistant CML and Ph+ ALL. Future trends investigating prediction of mechanisms of resistance to AMN107, and how and where AMN107 is expected to fit into the overall picture for treatment of early-phase CML and imatinib-refractory and late-stage disease are discussed
Current challenges in software solutions for mass spectrometry-based quantitative proteomics
This work was in part supported by the PRIME-XS project, grant agreement number 262067, funded by the European Union seventh Framework Programme; The Netherlands Proteomics Centre, embedded in The Netherlands Genomics Initiative; The Netherlands Bioinformatics Centre; and the Centre for Biomedical Genetics (to S.C., B.B. and A.J.R.H); by NIH grants NCRR RR001614 and RR019934 (to the UCSF Mass Spectrometry Facility, director: A.L. Burlingame, P.B.); and by grants from the MRC, CR-UK, BBSRC and Barts and the London Charity (to P.C.
Cooperation, Norms, and Revolutions: A Unified Game-Theoretical Approach
Cooperation is of utmost importance to society as a whole, but is often
challenged by individual self-interests. While game theory has studied this
problem extensively, there is little work on interactions within and across
groups with different preferences or beliefs. Yet, people from different social
or cultural backgrounds often meet and interact. This can yield conflict, since
behavior that is considered cooperative by one population might be perceived as
non-cooperative from the viewpoint of another.
To understand the dynamics and outcome of the competitive interactions within
and between groups, we study game-dynamical replicator equations for multiple
populations with incompatible interests and different power (be this due to
different population sizes, material resources, social capital, or other
factors). These equations allow us to address various important questions: For
example, can cooperation in the prisoner's dilemma be promoted, when two
interacting groups have different preferences? Under what conditions can costly
punishment, or other mechanisms, foster the evolution of norms? When does
cooperation fail, leading to antagonistic behavior, conflict, or even
revolutions? And what incentives are needed to reach peaceful agreements
between groups with conflicting interests?
Our detailed quantitative analysis reveals a large variety of interesting
results, which are relevant for society, law and economics, and have
implications for the evolution of language and culture as well
Paradoxical co-existing base metal sulphides in the mantle: The multi-event record preserved in Loch Roag peridotite xenoliths, North Atlantic Craton
The role of the subcontinental lithospheric mantle as a source of precious metals for mafic magmas is contentious and, given the chalcophile (and siderophile) character of metals such as the platinum-group elements (PGE), Se, Te, Re, Cu and Au, the mobility of these metals is intimately linked with that of sulphur. Hence the nature of the host phase(s), and their age and stability in the subcontinental lithospheric mantle may be of critical importance. We investigate the sulphide mineralogy and sulphide in situ trace element compositions in base metal sulphides (BMS) in a suite of spinel lherzolite mantle xenoliths from northwest Scotland (Loch Roag, Isle of Lewis). This area is situated on the margin of the North Atlantic Craton which has been overprinted by a Palaeoproterozoic orogenic belt, and occurs in a region which has undergone magmatic events from the Palaeoproterozoic to the Eocene.
We identify two populations of co-existing BMS within a single spinel lherzolite xenolith (LR80) and which can also be recognised in the peridotite xenolith suite as a whole. Both populations consist of a mixture of Fe-Ni-Cu sulphide minerals, and we distinguished between these according to BMS texture, petrographic setting (i.e., location within the xenolith in terms of ‘interstitial’ or within feldspar-spinel symplectites, as demonstrated by X-ray Computed Microtomography) and in situ trace element composition. Group A BMS are coarse, metasomatic, have low concentrations of total PGE (< 40 ppm) and high (Re/Os)N (ranging 1 to 400). Group B BMS strictly occur within symplectites of spinel and feldspar, are finer-grained rounded droplets, with micron-scale PtS (cooperite), high overall total PGE concentrations (15–800 ppm) and low (Re/Os)N ranging 0.04 to 2. Group B BMS sometimes coexist with apatite, and both the Group B BMS and apatite can preserve rounded micron-scale Ca-carbonate inclusions indicative of sulphide-carbonate-phosphate immiscibility. This carbonate-phosphate metasomatic association appears to be important in forming PGE-rich sulphide liquids, although the precise mechanism for this remains obscure. As a consequence of their position within the symplectites, Group B BMS are particularly vulnerable to being incorporated in ascending mantle-derived magmas (either by melting or physical entrainment). Based on the cross-cutting relationships of the symplectites, it is possible to infer the relative ages of each metasomatic BMS population. We tally these with major tectono-magmatic events for the North Atlantic region by making comparisons to carbonatite events recorded in crustal and mantle rocks, and we suggest that the Pt-enrichment was associated with a pre-Carboniferous carbonatite episode. This method of mantle xenolith base metal sulphide documentation may ultimately permit the temporal and spatial mapping of the chalcophile metallogenic budget of the lithospheric mantle, providing a blueprint for assessing regional metallogenic potential.
Abbreviations:
NAC, North Atlantic Craton; GGF, Great Glen Fault; NAIP, North Atlantic Igneous Province; BPIP, British Palaeogene Igneous Province; SCLM, subcontinental lithospheric mantle; PGE, platinum-group elements; HSE, highly siderophile elements; BMS, base metal sulphid
Emergence of Spatial Structure in Cell Groups and the Evolution of Cooperation
On its own, a single cell cannot exert more than a microscopic influence on its immediate surroundings. However, via strength in numbers and the expression of cooperative phenotypes, such cells can enormously impact their environments. Simple cooperative phenotypes appear to abound in the microbial world, but explaining their evolution is challenging because they are often subject to exploitation by rapidly growing, non-cooperative cell lines. Population spatial structure may be critical for this problem because it influences the extent of interaction between cooperative and non-cooperative individuals. It is difficult for cooperative cells to succeed in competition if they become mixed with non-cooperative cells, which can exploit the public good without themselves paying a cost. However, if cooperative cells are segregated in space and preferentially interact with each other, they may prevail. Here we use a multi-agent computational model to study the origin of spatial structure within growing cell groups. Our simulations reveal that the spatial distribution of genetic lineages within these groups is linked to a small number of physical and biological parameters, including cell growth rate, nutrient availability, and nutrient diffusivity. Realistic changes in these parameters qualitatively alter the emergent structure of cell groups, and thereby determine whether cells with cooperative phenotypes can locally and globally outcompete exploitative cells. We argue that cooperative and exploitative cell lineages will spontaneously segregate in space under a wide range of conditions and, therefore, that cellular cooperation may evolve more readily than naively expected
Toward interoperable bioscience data
© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Nature Genetics 44 (2012): 121-126, doi:10.1038/ng.1054.To make full use of research data, the bioscience community needs to adopt technologies and reward mechanisms that support interoperability and promote the growth of an open 'data commoning' culture. Here we describe the prerequisites for data commoning and present an established and growing ecosystem of solutions using the shared 'Investigation-Study-Assay' framework to support that vision.The authors also acknowledge
the following funding sources in particular: UK
Biotechnology and Biological Sciences Research
Council (BBSRC) BB/I000771/1 to S.-A.S. and A.T.;
UK BBSRC BB/I025840/1 to S.-A.S.; UK BBSRC
BB/I000917/1 to D.F.; EU CarcinoGENOMICS
(PL037712) to J.K.; US National Institutes of Health
(NIH) 1RC2CA148222-01 to W.H. and the HSCI;
US MIRADA LTERS DEB-0717390 and Alfred P.
Sloan Foundation (ICoMM) to L.A.-Z.; Swiss Federal
Government through the Federal Office of Education
and Science (FOES) to L.B. and I.X.; EU Innovative
Medicines Initiative (IMI) Open PHACTS 115191 to
C.T.E.; US Department of Energy (DOE) DE-AC02-
06CH11357 and Arthur P. Sloan Foundation (2011-
6-05) to J.G.; UK BBSRC SysMO-DB2 BB/I004637/1
and BBG0102181 to C.G.; UK BBSRC BB/I000933/1
to C.S. and J.L.G.; UK MRC UD99999906 to J.L.G.;
US NIH R21 MH087336 (National Institute of Mental
Health) and R00 GM079953 (National Institute of
General Medical Science) to A.L.; NIH U54 HG006097
to J.C. and C.E.S.; Australian government through
the National Collaborative Research Infrastructure
Strategy (NCRIS); BIRN U24-RR025736 and BioScholar RO1-GM083871 to G.B. and the 2009 Super
Science initiative to C.A.S
Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models.
Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, the feasibility of these approaches for dominantly inherited diseases - where treatment may require reduction in the expression of a toxic mutant protein resulting from a gain-of-function allele - is unclear. Here we show the efficacy of allele-specific RNAi as a potential therapy for Charcot-Marie-Tooth disease type 2D (CMT2D), caused by dominant mutations in glycyl-tRNA synthetase (GARS). A de novo mutation in GARS was identified in a patient with a severe peripheral neuropathy, and a mouse model precisely recreating the mutation was produced. These mice developed a neuropathy by 3-4 weeks of age, validating the pathogenicity of the mutation. RNAi sequences targeting mutant GARS mRNA, but not wild-type, were optimized and then packaged into AAV9 for in vivo delivery. This almost completely prevented the neuropathy in mice treated at birth. Delaying treatment until after disease onset showed modest benefit, though this effect decreased the longer treatment was delayed. These outcomes were reproduced in a second mouse model of CMT2D using a vector specifically targeting that allele. The effects were dose dependent, and persisted for at least 1 year. Our findings demonstrate the feasibility of AAV9-mediated allele-specific knockdown and provide proof of concept for gene therapy approaches for dominant neuromuscular diseases
SN 2022crv: IIb, Or Not IIb: That is the Question
We present optical and near-infrared observations of SN~2022crv, a stripped
envelope supernova in NGC~3054, discovered within 12 hrs of explosion by the
Distance Less Than 40 Mpc Survey. We suggest SN~2022crv is a transitional
object on the continuum between SNe Ib and SNe IIb. A high-velocity hydrogen
feature (20,000 -- 16,000 ) was conspicuous in
SN~2022crv at early phases, and then quickly disappeared around maximum light.
By comparing with hydrodynamic modeling, we find that a hydrogen envelope of
\msun{} can reproduce the behaviour of the hydrogen feature
observed in SN~2022crv. The early light curve of SN~2022crv did not show
envelope cooling emission, implying that SN~2022crv had a compact progenitor
with extremely low amount of hydrogen. The analysis of the nebular spectra
shows that SN~2022crv is consistent with the explosion of a He star with a
final mass of 4.5 -- 5.6 \msun{} that has evolved from a 16 -- 22
\msun{} zero-age main sequence star in a binary system with about 1.0 -- 1.7
\msun{} of oxygen finally synthesized in the core. The high metallicity at the
supernova site indicates that the progenitor experienced a strong stellar wind
mass loss. In order to retain a small amount of residual hydrogen at such a
high metallicity, the initial orbital separation of the binary system is likely
larger than 1000~. The near-infrared spectra of SN~2022crv
show a unique absorption feature on the blue side of He I line at
1.005~m. This is the first time that such a feature has been
observed in a Type Ib/IIb, and could be due to \ion{Sr}{2}. Further detailed
modelling on SN~2022crv can shed light on the progenitor and the origin of the
mysterious absorption feature in the near infrared.Comment: 33 pages, 23 figures, submitted to Ap
COordination of Standards in MetabOlomicS (COSMOS): facilitating integrated metabolomics data access
Metabolomics has become a crucial phenotyping technique in a range of research fields including medicine, the life sciences, biotechnology and the environmental sciences. This necessitates the transfer of experimental information between research groups, as well as potentially to publishers and funders. After the initial efforts of the metabolomics standards initiative, minimum reporting standards were proposed which included the concepts for metabolomics databases. Built by the community, standards and infrastructure for metabolomics are still needed to allow storage, exchange, comparison and re-utilization of metabolomics data. The Framework Programme 7 EU Initiative ‘coordination of standards in metabolomics’ (COSMOS) is developing a robust data infrastructure and exchange standards for metabolomics data and metadata. This is to support workflows for a broad range of metabolomics applications within the European metabolomics community and the wider metabolomics and biomedical communities’ participation. Here we announce our concepts and efforts asking for re-engagement of the metabolomics community, academics and industry, journal publishers, software and hardware vendors, as well as those interested in standardisation worldwide (addressing missing metabolomics ontologies, complex-metadata capturing and XML based open source data exchange format), to join and work towards updating and implementing metabolomics standards
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