Mutations in the kinase domain of epidermal growth factor receptor (EGFR) are associated with clinical responsiveness to gefitinib in patients with non-small-cell lung cancers (NSCLC). Recently, we ...have identified many novel EGFR mutations in NSCLC tissues. In this study, we found that gefitinib could suppress the tyrosine phosphorylation of most EGFR mutants better than the wild-type receptor. However, gefitinib had quite variable growth-suppressive effects on different EGFR mutant-expressing cells. All tested EGFR mutants have high basal phosphorylation at multiple tyrosine residues. Upon EGF stimulation, the mutated EGFRs did not have apparently stronger phosphorylation at tyrosines 845, 992, 1,068, and 1,173 than the wild-type receptor. However, stronger phosphorylation at tyrosine 1,045 was observed in the S768I, L861Q, E709G, and G719S mutants. The E746-A750 deletion mutant was less responsive to EGF than the wild-type and other mutant receptors. The S768I, L861Q, E709G, and G719S mutants were refractory to EGF-induced ubiquitination and had more sustained tyrosine phosphorylation. E709G and G719S also lacked EGF-induced receptor downregulation. Our results indicate that, in addition to sensitivity to gefitinib, EGFR mutations also caused various changes in EGFR's regulatory mechanisms, which may contribute to the constitutive activation of EGFR mutants and oncogenesis in NSCLC.
We present an updated mid-infrared (MIR) versus X-ray correlation for the local active galactic nuclei (AGN) population based on the high angular resolution 12 and 18μm continuum fluxes from the AGN ...subarcsecond MIR atlas and 2–10 keV and 14–195 keV data collected from the literature. We isolate a sample of 152 objects with reliable AGN nature and multi-epoch X-ray data and minimal MIR contribution from star formation. Although the sample is not homogeneous or complete, we show that our results are unlikely to be affected by significant biases. The MIR–X-ray correlation is nearly linear and within a factor of 2 independent of the AGN type and the wavebands used. The observed scatter is <0.4 dex. A possible flattening of the correlation slope at the highest luminosities probed (∼1045 erg s−1) towards low MIR luminosities for a given X-ray luminosity is indicated but not significant. Unobscured objects have, on average, an MIR–X-ray ratio that is only ≤0.15 dex higher than that of obscured objects. Objects with intermediate X-ray column densities (22 < log N
H < 23) actually show the highest MIR–X-ray ratio on average. Radio-loud objects show a higher mean MIR–X-ray ratio at low luminosities while the ratio is lower than average at high luminosities. This may be explained by synchrotron emission from the jet contributing to the MIR at low luminosities and additional X-ray emission at high luminosities. True Seyfert 2 candidates do not show any deviation from the general behaviour suggesting that they possess a dusty obscurer as in other AGN. Double AGN also do not deviate. Finally, we show that the MIR–X-ray correlation can be used to investigate the AGN nature of uncertain objects. Specifically, we give equations that allow us to determine the intrinsic 2–10 keV luminosities and column densities for objects with complex X-ray properties to within 0.34 dex. These techniques are applied to the uncertain objects of the remaining AGN MIR atlas, demonstrating the usefulness of the MIR–X-ray correlation as an empirical tool.
Background/Aim
A link between an impaired intestinal barrier, endotoxemia, and the pathogenesis of metabolic diseases, such as type 2 diabetes mellitus (T2DM), has been proposed. In previous work, we ...have demonstrated that the tight junction (TJ)-mediated intestinal barrier in ileum/colon was marginally changed in prediabetic mice; therefore, it does not seem to mainly contribute to the T2DM onset. In this study, the TJ-mediated epithelial barrier in the duodenum and jejunum was evaluated in mice during the development of type 2 prediabetes.
Methods/Results
HF diet induced prediabetes after 60 days associated with a significant rise in intestinal permeability to the small-sized marker Lucifer yellow in these mice, with no histological signs of mucosal inflammation or rupture of the proximal intestine epithelium. As revealed by immunofluorescence, TJ proteins, such as claudins-1, -2, -3, and ZO-1, showed a significant decrease in junctional content in duodenum and jejunum epithelia, already after 15 days of treatment, suggesting a rearrangement of the TJ structure. However, no significant change in total cell content of these proteins was observed in intestinal epithelium homogenates, as assessed by immunoblotting. Despite the changes in intestinal permeability and TJ structure, the prediabetic mice showed similar LPS, zonulin, and TNF-α levels in plasma or adipose tissue, and in intestinal segments as compared to the controls.
Conclusion
Disruption of the TJ-mediated paracellular barrier in the duodenum and jejunum is an early event in prediabetes development, which occurs in the absence of detectable endotoxemia/inflammation and may contribute to the HF diet-induced increase in intestinal permeability.
Atomic and molecular data for the transitions of a number of astrophysically interesting species are summarized, including energy levels, statistical weights, Einstein A-coefficients and collisional ...rate coefficients. Available collisional data from quantum chemical calculations and experiments are extrapolated to higher energies (up to E/k similar to 1000 K). These data, which are made publically available through the WWW at http://www.strw.leidenuniv.nl/ similar to moldata, are essential input for non-LTE line radiative transfer programs. An online version of a computer program for performing statistical equilibrium calculations is also made available as part of the database. Comparisons of calculated emission lines using different sets of collisional rate coefficients are presented. This database should form an important tool in analyzing observations from current and future (sub)millimetre and infrared telescopes.
Introduction
The Core Outcome Measures Index for the back (COMI-back) is a very brief instrument for assessing the main outcomes of importance to patients with back problems (pain, function, ...symptom-specific well-being, quality of life, disability). However, it might be expected to be less responsive than a disease-specific instrument when evaluating specific pathologies. In patients with adult spinal deformity, we compared the performance of COMI-back with the widely accepted SRS-22 questionnaire.
Methods
At baseline and 12 months after non-operative (
N
= 121) and surgical (
N
= 83) treatment, patients (175 F, 29 M) completed the following: COMI-back, SRS-22, Oswestry Disability Index (ODI) and SF-36 PCS. At 12 months' follow-up, patients also indicated on a 15-point Global Rating of Change Scale (GRCS) how their back problem had changed relative to 1 year ago. Construct validity for the COMI-back was assessed by the correlation between its scores and those of the comparator instruments; responsiveness was assessed with receiver operating characteristics (ROC) analysis of COMI-back change scores versus the criterion ‘treatment success’ (dichotomized GRCS).
Results
Baseline values for the COMI-back showed significant (
p
< 0.0001) correlations with SRS-22 (
r
= −0.85), ODI (
r
= 0.83), and SF-36 PCS (
r
= −0.82) scores; significantly worse scores for all measures were recorded in the surgical group. The correlation between the change scores (baseline to 12 months) for COMI and SRS-22 was 0.74, and between each of these change scores and the external criterion of treatment success were: COMI-back,
r
= 0.58; SRS-22,
r
= −0.58 (each
p
< 0.0001). The ROC areas under the curve for the COMI-back and SRS-22 change scores were 0.79 and 0.82, respectively.
Conclusion
Both baseline and change scores for the COMI-back correlated strongly with those of the SRS-22, and differed significantly in surgical and non-operative patients, suggesting good construct validity. With the “change in the back problem” serving as external criterion, COMI-back showed similar external responsiveness to SRS-22. The COMI-back was well able to detect important change. Coupled with its brevity, which minimizes patient burden, these favourable psychometric properties suggest the COMI-back is a suitable instrument for use in registries and can serve as a valid instrument in clinical studies emerging from such data pools.
In this work, the fracture behaviour of repaired honeycomb/carbon-epoxy sandwich panels under edgewise compression and three-point bending loading was analysed. Assuming the occurrence of damage ...resulting from a complete perforation leading to an open hole, the followed repair strategy consists of plug filling the core hole and considering two scarf patches with an angle of 10° in order to repair the damaged skins. Experimental tests were performed on undamaged and repaired situations in order to address the alteration in the failure modes and assess the repair efficiency. It was observed that repair recovers a large part of the mechanical properties of the corresponding undamaged case. Additionally, a three-dimensional finite element analysis incorporating a mixed-mode I + II + III cohesive zone model was performed for the repaired cases. Cohesive elements were considered in the several critical regions prone to damage development. The failure modes and the resultant load-displacement curves obtained numerically were compared with the experimental ones. It was concluded that the numerical model is suitable for estimating the fracture behaviour of sandwich panel repairs.
ABSTRACT
To understand how phosphorus (P)-bearing molecules are formed in star-forming regions, we have analysed the Atacama Large Millimeter/Submillimeter Array (ALMA) observations of PN and PO ...towards the massive star-forming region AFGL 5142, combined with a new analysis of the data of the comet 67P/Churyumov–Gerasimenko taken with the Rosetta Orbiter Spectrometer for Ion and Neutral Analysis (ROSINA) instrument onboard Rosetta. The ALMA maps show that the emission of PN and PO arises from several spots associated with low-velocity gas with narrow linewidths in the cavity walls of a bipolar outflow. PO is more abundant than PN in most of the spots, with the PO/PN ratio increasing as a function of the distance to the protostar. Our data favour a formation scenario in which shocks sputter phosphorus from the surface of dust grains, and gas-phase photochemistry induced by UV photons from the protostar allows efficient formation of the two species in the cavity walls. Our analysis of the ROSINA data has revealed that PO is the main carrier of P in the comet, with PO/PN > 10. Since comets may have delivered a significant amount of prebiotic material to the early Earth, this finding suggests that PO could contribute significantly to the phosphorus reservoir during the dawn of our planet. There is evidence that PO was already in the cometary ices prior to the birth of the Sun, so the chemical budget of the comet might be inherited from the natal environment of the Solar system, which is thought to be a stellar cluster including also massive stars.
Introduction
The Oswestry Disability Index (ODI) and the Core Outcome Measures Index (COMI) are two commonly used self-rating outcome instruments in patients with lumbar spinal disorders. No formal ...crosswalk between them exists that would otherwise allow the scores of one to be interpreted in terms of the other. We aimed to create such a mapping function.
Methods
We performed a secondary analysis of ODI and COMI data previously collected from 3324 patients (57 ± 17y; 60.3% female) at baseline and 1y after surgical or conservative treatment. Correlations between scores and Cohen’s kappa for agreement (
κ
) regarding achievement of the minimal clinically important change (MCIC) score on each instrument (ODI, 12.8 points; COMI, 2.2 points) were calculated, and regression models were built. The latter were tested for accuracy in an independent set of registry data from 634 patients (60 ± 15y; 56.8% female).
Results
All pairs of measures were significantly positively correlated (baseline, 0.73; 1y follow-up (FU), 0.84; change-scores, 0.73). MCIC for COMI was achieved in 53.9% patients and for ODI, in 52.4%, with 78% agreement on an individual basis (
κ
= 0.56). Standard errors for the regression slopes and intercepts were low, indicating excellent prediction at the group level, but root mean square residuals (reflecting individual error) were relatively high. ODI was predicted as COMI × 7.13–4.20 (at baseline), COMI × 6.34 + 2.67 (at FU) and COMI × 5.18 + 1.92 (for change-score); COMI was predicted as ODI × 0.075 + 3.64 (baseline), ODI × 0.113 + 0.96 (FU), and ODI × 0.102 + 1.10 (change-score). ICCs were 0.63–0.87 for derived versus actual scores.
Conclusion
Predictions at the group level were very good and met standards justifying the pooling of data. However, we caution against using individual values for treatment decisions, e.g. attempting to monitor patients over time, first with one instrument and then with the other, due to the lower statistical precision at the individual level. The ability to convert scores via the developed mapping function should open up more centres/registries for collaboration and facilitate the combining of data in meta-analyses.
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