Conservationists are increasingly engaging with the concept of human well‐being to improve the design and evaluation of their interventions. Since the convening of the influential Sarkozy Commission ...in 2009, development researchers have been refining conceptualizations and frameworks to understand and measure human well‐being and are starting to converge on a common understanding of how best to do this. In conservation, the term human well‐being is in widespread use, but there is a need for guidance on operationalizing it to measure the impacts of conservation interventions on people. We present a framework for understanding human well‐being, which could be particularly useful in conservation. The framework includes 3 conditions; meeting needs, pursuing goals, and experiencing a satisfactory quality of life. We outline some of the complexities involved in evaluating the well‐being effects of conservation interventions, with the understanding that well‐being varies between people and over time and with the priorities of the evaluator. Key challenges for research into the well‐being impacts of conservation interventions include the need to build up a collection of case studies so as to draw out generalizable lessons; harness the potential of modern technology to support well‐being research; and contextualize evaluations of conservation impacts on well‐being spatially and temporally within the wider landscape of social change. Pathways through the smog of confusion around the term well‐being exist, and existing frameworks such as the Well‐being in Developing Countries approach can help conservationists negotiate the challenges of operationalizing the concept. Conservationists have the opportunity to benefit from the recent flurry of research in the development field so as to carry out more nuanced and locally relevant evaluations of the effects of their interventions on human well‐being.
Within the field of environmental management and conservation, the concept of well-being is starting to gain traction in monitoring the socio-economic and cultural impact of interventions on local ...people. Here we consider the practical trade-offs policy makers and practitioners must navigate when utilizing the concept of well-being in environmental interventions. We first review current concepts of well-being before considering the need to balance the complexity and practical applicability of the definition used and to consider both positive and negative components of well-being. A key determinant of how well-being is operationalized is the identity of the organization wishing to monitor it. We describe the trade-offs around the external and internal validity of different approaches to measuring well-being and the relative contributions of qualitative and quantitative information to understanding well-being. We explore how these trade-offs may be decided as a result of a power struggle between stakeholders. Well-being is a complex, multi-dimensional, dynamic concept that cannot be easily defined and measured. Local perspectives are often missed during the project design process as a result of the more powerful voices of national governments and international NGOs, so for equity and local relevance it is important to ensure these perspectives are represented at a high level in project design and implementation.
Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are ...thought to be unaffected. We show that the brains of adult C57BL6 wild-type mice treated with a single systemic dose of MAM acetate display DNA damage (O⁶-methyldeoxyguanosine lesions, O⁶-mG) that remains constant up to 7 days post-treatment. By contrast, MAM-treated mice lacking a functional gene encoding the DNA repair enzyme O⁶-mG DNA methyltransferase (MGMT) showed elevated O⁶-mG DNA damage starting at 48 hours post-treatment. The DNA damage was linked to changes in the expression of genes in cell-signaling pathways associated with cancer, human neurodegenerative disease, and neurodevelopmental disorders. These data are consistent with the established developmental neurotoxic and carcinogenic properties of MAM in rodents. They also support the hypothesis that early-life exposure to MAM-glucoside (cycasin) has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for food or medicine, or both. These findings suggest environmental genotoxins, specifically MAM, target common pathways involved in neurodegeneration and cancer, the outcome depending on whether the cell can divide (cancer) or not (neurodegeneration). Exposure to MAM-related environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer's disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A series of 6- and 7-acrylamide derivatives of the 4-(phenylamino)quinazoline and -pyridopyrimidine classes of epidermal growth factor receptor (EGFR) inhibitors were prepared from the corresponding ...amino compounds by reaction with either acryloyl chloride/base or acrylic acid/1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. All of the 6-acrylamides, but only the parent quinazoline 7-acrylamide, were irreversible inhibitors of the isolated enzyme, confirming that the former are better-positioned, when bound to the enzyme, to react with the critical cysteine-773. Quinazoline, pyrido3,4-dpyrimidine, and pyrido3,2-dpyrimidine 6-acrylamides were all irreversible inhibitors and showed similar high potencies in the enzyme assay (likely due to titration of the available enzyme). However the pyrido3,2-dpyrimidine analogues were 2−6-fold less potent than the others in a cellular autophosphorylation assay for EGFR in A431 cells. The quinazolines were generally less potent overall toward inhibition of heregulin-stimulated autophosphorylation of erbB2 (in MDA-MB-453-cells), whereas the pyridopyrimidines were equipotent. Selected compounds were evaluated in A431 epidermoid and H125 non-small-cell lung cancer human tumor xenografts. The compounds showed better activity when given orally than intraperitoneally. All showed significant tumor growth inhibition (stasis) over a dose range. The poor aqueous solubility of the compounds was a drawback, requiring formulation as fine particulate emulsions.
Following the discovery of the very high inhibitory ability of the 4-(3-bromophenyl)aminoquinazolines against the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) (e.g., 3, ...IC50 0.029 nM), four series of related pyridodpyrimidines bearing electron-donating groups at the 6- or 7-positions have been synthesized and evaluated. The compounds were prepared by nucleophilic substitution of the corresponding 6- and 7-fluoro analogues. While members of all series showed potent inhibitory activity against isolated EGFR, there were important differences between the different isomeric pyridodpyrimidines and the parent quinazolines. Overall, the 3,4-d and 4,3-d series were the most potent, followed by the 3,2-d compounds, with the 2,3-d analogues being least active. Whereas in the parent quinazoline series the addition of steric bulk to a 6- or 7-NH2 substituent (i.e., NHMe and NMe2 groups) dramatically decreased potency, no such trend was discernable in the 3,2-d series. Furthermore, in the 7-substituted pyrido4,3-d- and 6-substituted pyrido3,4-dpyrimidine series, and to a limited extent in the 7-substituted pyrido2,3-d series, such substitution increased potency dramatically, to the extent that the 7-(methylamino)pyrido4,3-dpyrimidine (5f) (IC50 0.13 nM) and 6-(methylamino)pyrido3,4-dpyrimidine (7f) (IC50 0.008 nM) constitute important new leads. Selected compounds were evaluated for their ability to inhibit EGFR autophosphorylation in A431 cells, and a positive quantitative correlation was found between this activity and inhibitory activity against the isolated enzyme.
A new route to N-1-substituted pyrazolo- and pyrroloquinazolines has been developed from the known quinazolones 19 and 23, via conversion to the corresponding thiones, S-methylation to the ...thioethers, N-1-alkylation, and coupling with 3-bromoaniline. C-3-Substituted pyrroloquinazolines were prepared by Mannich base chemistry. A series of compounds bearing solubilizing side chains at these positions has been prepared and evaluated for inhibition of the tyrosine kinase activity of the isolated epidermal growth factor receptor (EGFR) and of its autophosphorylation in EGF-stimulated A431 cells. Several analogues, particularly C-3-substituted pyrroloquinazolines, retained high potency in both assays. A model for the binding of the general class of 4-anilinoquinazolines to the EGFR was constructed from structural information (particularly for the catalytic subunit of the cAMP-dependent protein kinase) and structure−activity relationships (SAR) in the series. In this model, the pyrrole ring in pyrroloquinazolines (and the 6- and 7-positions of quinazoline and related pyridopyrimidine inhibitors) occupies the entrance of the ATP binding pocket of the enzyme, with the pyrrole nitrogen located at the bottom of the cleft and the pyrrole C-3 position pointing toward a pocket corresponding to the ribose binding site of ATP. This allows considerable bulk tolerance for C-3 substituents and lesser but still significant bulk tolerance for N-1 substituents. The observed high selectivity of these compounds for binding to EGFR over other similar tyrosine kinases is attributed to the 4-anilino ring binding in an adjacent hydrophobic pocket which has an amino acid composition unique to the EGFR. The SAR seen for inhibition of the isolated enzyme by the pyrazolo- and pyrroloquinazolines discussed here is fully consistent with this binding model. For the N-1-substituted compounds, inhibition of autophosphorylation in A431 cells correlates well with inhibition of the isolated enzyme, as seen previously for related pyridopyrimidines. However, the C-3-substituted pyrroloquinazolines show unexpectedly high potencies in the autophosphorylation assay, making them of particular interest.
At least 28 randomised, controlled trials have compared outcomes of surgery for rectal cancer combined with preoperative or postoperative radiotherapy with those of surgery alone. We have done a ...collaborative meta-analysis of these results to give a more balanced view of the total evidence and to increase statistical precision.
We centrally checked and analysed individual patient data from 22 randomised comparisons between preoperative (6350 patients in 14 trials) or postoperative (2157 in eight trials) radiotherapy and no radiotherapy for rectal cancer.
Overall survival was only marginally better in patients who were allocated to radiotherapy than in those allocated to surgery alone (62%
vs 63% died; p=0·06). Rates of apparently curative resection were not improved by preoperative radiotherapy (85% radiotherapy
vs 86% control). Yearly risk of local recurrence was 46% (SE 6) lower in those who had preoperative radiotherapy than in those who had surgery alone (p=0·00001), and 37% (10) lower in those who had postoperative treatment than those who had surgery alone (p=0·002). Fewer patients who had preoperative radiotherapy died from rectal cancer than did those who had surgery alone (45%
vs 50%, respectively, p=0·0003), but early (≤1 year after treatment) deaths from other causes increased (8%
vs 4% died, p<0·0001).
Preoperative radiotherapy (at biologically effective doses ≥30 Gy) reduces risk of local recurrence and death from rectal cancer. If safety can be improved without compromising effectiveness, then overall survival would be moderately improved by use of preoperative radiotherapy, especially for young, high risk patients. Postoperative radiotherapy also reduces local recurrence, but short preoperative radiation schedules seem to be at least as effective as longer schedules.
Following the discovery of 4-(3-bromophenyl)amino-6,7-dimethoxyquinazoline (4; PD 153035) as an extremely potent (IC50 0.025 nM) inhibitor of the tyrosine kinase activity of the epidermal growth ...factor receptor (EGFR), several fused tricyclic quinazoline analogues have been prepared and evaluated for their ability to inhibit the enzyme. The most potent compound was the linear imidazo4,5-gquinazoline (8), which exhibited an IC50 of 0.008 nM for inhibition of phosphorylation of a fragment of phospholipase C-γ1 as substrate. While N-methyl analogues of 8 showed similar potency, analogous N-2-(dimethylamino)ethyl derivatives were less effective. The next most potent compounds were the linear pyrazoloquinazolines (19 and 20) (IC50s 0.34 and 0.44 nM) and pyrroloquinazoline (21) (IC50 0.44 nM), while several other linear tricyclic ring systems of similar geometry to 8 (triazolo-, thiazolo-, and pyrazinoquinazolines) were less effective. In the imidazo4,5-gquinazoline and pyrroloquinazoline series, the corresponding angular isomers were also much less effective than the linear ones. These results are consistent with structure−activity relationship studies previously developed for the 4-(3-bromophenyl)aminoquinazolines, which suggested that small electron-donating substituents at the 6- and 7-positions were desirable for high potency. Cellular studies of the linear imidazoloquinazoline 8 show that it can enter cells and rapidly and very selectively shut down EGF-stimulated signal transmission by binding competitively at the ATP site of the EGFR.
A novel single-particle technique to measure emittance has been developed and used to characterise seventeen different muon beams for the Muon Ionisation Cooling Experiment (MICE). The muon beams, ...whose mean momenta vary from 171 to 281 MeV/
c
, have emittances of approximately 1.2–2.3
π
mm-rad horizontally and 0.6–1.0
π
mm-rad vertically, a horizontal dispersion of 90–190 mm and momentum spreads of about 25 MeV/
c
. There is reasonable agreement between the measured parameters of the beams and the results of simulations. The beams are found to meet the requirements of MICE.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gene expression profiling is a widely used technique with data from the majority of published microarray studies being publicly available. These data are being used for meta-analyses and in silico ...discovery; however, the comparability of toxicogenomic data generated in multiple laboratories has not been critically evaluated. Using the power of prospective multilaboratory investigations, seven centers individually conducted a common toxicogenomics experiment designed to advance understanding of molecular pathways perturbed in liver by an acute toxic dose of N-acetyl-p-aminophenol (APAP) and to uncover reproducible genomic signatures of APAP-induced toxicity. The nonhepatotoxic APAP isomer N-acetyl-m-aminophenol was used to identify gene expression changes unique to APAP. Our data show that c-Myc is induced by APAP and that c-Myc–centered interactomes are the most significant networks of proteins associated with liver injury. Furthermore, sources of error and data variability among Centers and methods to accommodate this variability were identified by coupling gene expression with extensive toxicological evaluation of the toxic responses. We show that phenotypic anchoring of gene expression data is required for biologically meaningful analysis of toxicogenomic experiments.
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