Gleevec (STI-571) inhibits lung cancer cell growth (A549) and potentiates the cisplatin effect in vitro

BACKGROUND: Gleevec (aka STI571, Imatinib) is a recently FDA approved anti-tumor drug for chronic myelogenous leukemia. Gleevec binds specifically to BCR-ABL tyrosine kinase and inhibit the tyrosine kinase activity. It cross-reacts with another two important membrane tyrosine kinase receptors, c-kit and PDGF receptors. We sought to investigate if Gleevec has a potential role in treatment of non-small cell lung cancer. RESULTS: We have shown that Gleevec alone can inhibit the A549 lung cancer cell growth in dose-dependent manner, and the optimal concentration of Gleevec inhibition of A549 cell growth is at the range of 2–3 μM (IC50). We have also shown that A549 cells are resistant to cisplatin treatment (IC50 64 μM). Addition of Gleevec to the A549 cells treated with cisplatin resulted in a synergistic cell killing effect, suggesting that Gleevec can potentiate the effect of cisplatin on A549 cells. We also showed that the A549 lung cancer cells expresses the platelet derived growth factor receptor α, and the inhibitory effects of Gleevec on A549 cells is likely mediated through inhibition of PDGFR α phosphorylation. We further tested 33 lung cancer patients' tumor specimens to see the frequency of PDGFR-α expression by tissue micro-arrays and immunohistochemistry. We found that 16 of the 18 squamous carcinomas (89%), 11 of the 11 adenocarcinomas (100%), and 4 of the 4 small cell lung cancers (100%) expressed PDGFR-α. CONCLUSION: These results suggest a potential role of Gleevec as adjuvant therapeutic agent for treatment of non-small cell lung cancer

Unlocking a diazirine long-lived nuclear singlet state via photochemistry : NMR detection and lifetime of an unstabilized diazo-compound

Diazirines are important for photoaffinity labelling and their photoisomerization is relatively well known. This work shows how hyperpolarized NMR spectroscopy can be used to characterise an unstable diazo-compound formed via photoisomerization of a 15N2-labelled silyl-ether substituted diazirine. This diazirine is prepared in a nuclear spin singlet state via catalytic transfer of spin order from para-hydrogen. The active hyperpolarization catalyst is characterised to provide insight into the mechanism. The photochemical isomerisation of the diazirine into the diazo-analogue allows the NMR invisible nuclear singlet state of the parent compound to be probed. The identity of the diazo-species is confirmed by trapping with N-phenyl maleimide via a cycloaddition reaction to afford bicyclic pyrazolines that also show singlet state character. The presence of singlet states in the diazirine and the diazo-compound are validated by comparison of experimental nutation behaviour with theoretical simulation. The magnetic state lifetime of the diazo-compound is determined as 12 ± 1 s in CD3OD solution at room temperature whereas its chemical lifetime is measured as 100 ± 5 s by related hyperpolarized NMR studies. Indirect evidence for the generation of the photoproduct para-N2 is presented

Shared leadership and group identification in healthcare: : The leadership beliefs of clinicians working in interprofessional teams

This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Interprofessional Care on 28 February 2017, available online: http://www.tandfonline.com/doi/full/10.1080/13561820.2017.1280005.Despite the proposed benefits of applying shared and distributed leadership models in healthcare, few studies have explored the leadership beliefs of clinicians and ascertained whether differences exist between professions. The current paper aims to address these gaps and additionally, examine whether clinicians’ leadership beliefs are associated with the strength of their professional and team identifications. An online survey was responded to by 229 healthcare workers from community interprofessional teams in mental health settings across the East of England. No differences emerged between professional groups in their leadership beliefs; all professions reported a high level of agreement with shared leadership. A positive association emerged between professional identification and shared leadership i.e. participants who expressed the strongest level of profession identification also reported the greatest agreement with shared leadership. The same association was demonstrated for team identification and shared leadership. The findings highlight the important link between group identification and leadership beliefs, suggesting that strategies that promote strong professional and team identifications in interprofessional teams are likely to be conducive to clinicians supporting principles of shared leadership. Future research is needed to strengthen this link and examine the leadership practices of healthcare workers.Peer reviewe

Research and Education in Computational Science and Engineering

Over the past two decades the field of computational science and engineering (CSE) has penetrated both basic and applied research in academia, industry, and laboratories to advance discovery, optimize systems, support decision-makers, and educate the scientific and engineering workforce. Informed by centuries of theory and experiment, CSE performs computational experiments to answer questions that neither theory nor experiment alone is equipped to answer. CSE provides scientists and engineers of all persuasions with algorithmic inventions and software systems that transcend disciplines and scales. Carried on a wave of digital technology, CSE brings the power of parallelism to bear on troves of data. Mathematics-based advanced computing has become a prevalent means of discovery and innovation in essentially all areas of science, engineering, technology, and society; and the CSE community is at the core of this transformation. However, a combination of disruptive developments---including the architectural complexity of extreme-scale computing, the data revolution that engulfs the planet, and the specialization required to follow the applications to new frontiers---is redefining the scope and reach of the CSE endeavor. This report describes the rapid expansion of CSE and the challenges to sustaining its bold advances. The report also presents strategies and directions for CSE research and education for the next decade.Comment: Major revision, to appear in SIAM Revie

The Structure of Pre-transitional Protoplanetary Disks I: Radiative Transfer Modeling of the Disk+Cavity in the PDS 70 system

Through detailed radiative transfer modeling, we present a disk+cavity model to simultaneously explain both the SED and Subaru H-band polarized light imaging for the pre-transitional protoplanetary disk PDS 70. Particularly, we are able to match not only the radial dependence, but also the absolute scale, of the surface brightness of the scattered light. Our disk model has a cavity 65 AU in radius, which is heavily depleted of sub-micron-sized dust grains, and a small residual inner disk which produces a weak but still optically thick NIR excess in the SED. To explain the contrast of the cavity edge in the Subaru image, a factor of ~1000 depletion for the sub-micron-sized dust inside the cavity is required. The total dust mass of the disk may be on the order of 1e-4 M_sun, only weakly constrained due to the lack of long wavelength observations and the uncertainties in the dust model. The scale height of the sub-micron-sized dust is ~6 AU at the cavity edge, and the cavity wall is optically thick in the vertical direction at H-band. PDS 70 is not a member of the class of (pre-)transitional disks identified by Dong et al. (2012), whose members only show evidence of the cavity in the millimeter-sized dust but not the sub-micron-sized dust in resolved images. The two classes of (pre-)transitional disks may form through different mechanisms, or they may just be at different evolution stages in the disk clearing process.Comment: 28 pages (single column), 7 figures, 1 table, ApJ accepte

Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers

A special gift we bestow on you for being representative of us: Considering leader

Two experiments tested hypotheses, derived from social identity and self-categorization theories, regarding the attribution of charisma to leaders. In Experiment I (N = 203), in-group prototypical leaders were attributed greater levels of charisma and were perceived to be more persuasive than in-group non-prototypical leaders. In Experiment 2 (N = 220), leaders described with in-group stereotypical characteristics were attributed relatively high levels of charisma regardless of their group-oriented versus exchange rhetoric. Leaders described with out-group stereotypical characteristics, however, had to employ group-oriented rhetoric to be attributed relatively high levels of charisma. We conclude that leadership emerges from being representative of 'us'; charisma may, indeed, be a special gift, but it is one bestowed on group members by group members for being representative of, rather than distinct from, the group itself. © 2006 The British Psychological Society

The Far-Infrared Spectral Energy Distributions of X-ray-selected Active Galaxies

[Abridged] We present ISO far-infrared (IR) observations of 21 hard X-ray selected AGN from the HEAO-1 A2 sample. We compare the far-IR to X-ray spectral energy distributions (SEDs) of this sample with various radio and optically selected AGN samples. The hard-X-ray selected sample shows a wider range of optical/UV shapes extending to redder near-IR colors. The bluer objects are Seyfert 1s, while the redder AGN are mostly intermediate or type 2 Seyferts. This is consistent with a modified unification model in which the amount of obscuring material increases with viewing angle and may be clumpy. Such a scenario, already suggested by differing optical/near-IR spectroscopic and X-ray AGN classifications, allows for different amounts of obscuration of the continuum emission in different wavebands and of the broad emission line region which results in a mixture of behaviors for AGN with similar optical emission line classifications. The resulting limits on the column density of obscuring material through which we are viewing the redder AGN are 100 times lower than for the standard optically thick torus models. The resulting decrease in optical depth of the obscuring material allows the AGN to heat more dust at larger radial distances. We show that an AGN-heated, flared, dusty disk with mass 10^9 solar and size of few hundred pc is able to generate optical-far-IR SEDs which reproduce the wide range of SEDs present in our sample with no need for an additional starburst component to generate the long-wavelength, cooler part of the IR continuum.Comment: 40 pages, 14 figures, accepted for publication in Astrophysical Journal, V. 590, June 10, 200

RITUAL, TIME, AND ENTERNITY

It is argued here that the construction of time and eternity are among ritual's entailments. In dividing continuous duration into distinct periods ritual distinguishes two temporal conditions: (1) that prevailing in mundane periods and (2) that prevailing during the intervals between them. Differences in the frequency, length, and relationship among the rituals constituting different liturgical orders are considered, as are differences between mundane periods and ritual's intervals with respect to social relations, cognitive modes, meaningfulness, and typical interactive frequencies. Periods, it is observed, relate to intervals as everchanging to never-changing, and close relationships of never changing to eternity, eternity to sanctity, and sanctity to truth are proposed. In the argument that ritual's “times out of time” really are outside mundane time, similarities to the operations of digital computers and Herbert Simon's discussion of interaction frequencies in the organization of matter are noted.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72989/1/j.1467-9744.1992.tb00996.x.pd