MMP-9 and the epidermal growth factor signal pathway in non-small cell lung cancer

Background Matrix metalloproteinase (MMP)-9 is an endopeptidase that digests basement membrane type-IV collagen. Enhanced expression has been related to tumour progression in a number of systems. The control of MMP expression is complex, but recently epidermal growth actor receptor (EGFR) activity has been implicated in up-regulation of MMP-9 in tumour cells in vitro. Aims To evaluate interrelations between MMP-9 and EGFR expression in non-small cell lung cancer (NSCLC) and to assess the impact of expression on survival. Methods This is a retrospective study of 152 patients who underwent resection for stage I-IIIa NSCLC with a post-operative survival >60 days. Minimum follow-up was 2 years. Standard ABC immunohistochemistry was performed on 4μm paraffin-embedded sections from the tumour periphery using monoclonal antibodies to MMP-9 and EGFR. Results: MMP-9 was expressed in the tumour cells of 79/152 (52%) cases. EGFR expression was found in 86/152 (57%) cases [membranous 51/152 (34%), cytoplasmic 35/152 (23%)]. MMP-9 expression was associated with poor outcome (p=0.04). Membranous, cytoplasmic and overall EGFR expression were not associated with outcome (p=0.29, p=0.85 and p=0.41 respectively). There was a strong correlation between MMP-9 expression and EGFR expression (p=0.001) and EGFR membranous expression (p=0.01) but not with cytoplasmic EGFR expression (p=0.28). Co-expression of MMP-9 and EGFR (36%) conferred a worse prognosis (p=0.003). Subset analysis revealed only MMP-9 and membranous EGFR co-expression (22%) was associated with poor outcome (p=0.008). Conclusions Our results show that MMP-9 and EGFR are co-expressed in NSCLC. This finding suggests the EGFR signalling pathway may play an important role in the invasive behaviour of NSCLC via specific upregulation of MMP-9. The co-expression of these markers also confers a poor prognosis.

Do employees care about their relative income position? Behavioral evidence focusing on performance in professional team sport

Objective Do employees care about their relative (economic) position in comparison to their co-workers in an organization? And if so, does it raise or lower their performance? While the topic is widely discussed in the literature, behavioral evidence on these important questions is relatively rare. Methods This article explores the pay-performance relationship using a sports data set. The strength of analyzing such data is that sports tournaments take place in a very controlled environment that helps to isolate a relative income effect. Results Using two large unique data sets that cover 26 seasons in basketball and eight seasons in soccer (Bundesliga), we find considerable support for the idea that a relative income disadvantage is correlated with a decrease in individual performance. In addition, there does not seem to be any tolerance for income disparity based on the hope that such differences may signal that better times are ahead. Conclusions This suggests the need to consider the impact of the relative income position when designing pay-for-performance mechanisms within firms and teams.

An extracellular signal-regulated kinase 2 survival pathway mediates resistance of human mesothelioma cells to asbestos-induced injury

We hypothesized that normal human mesothelial cells acquire resistance to asbestos-induced toxicity via induction of one or more epidermal growth factor receptor (EGFR) - linked survival pathways (phosphoinositol-3-kinase/AKT/ mammalian target of rapamycin and extracellular signal - regulated kinase [ERK] 1/2) during simian virus 40 (SV40) transformation and carcinogenesis. Both isolated HKNM-2 mesothelial cells and a telomerase-immortalized mesothelial line (LP9/TERT-1) were more sensitive to crocidolite asbestos toxicity than an SV40 Tag-immortalized mesothelial line (MET5A) and malignant mesothelioma cell lines (HMESO and PPM Mill). Whereas increases in phosphorylation of AKT (pAKT) were observed in MET5A cells in response to asbestos, LP9/TERT-1 cells exhibited dose-related decreases in pAKT levels. Pretreatment with an EGFR phosphorylation or mitogen-activated protein kinase kinase 1/2 inhibitor abrogated asbestos-induced phosphorylated ERK (pERK) 1/2 levels in both LP9/TERT-1 and MET5A cells as well as increases in pAKT levels in MET5A cells. Transient transfection of small interfering RNAs targeting ERK1, ERK2, or AKT revealed that ERK1/2 pathways were involved in cell death by asbestos in both cell lines. Asbestos-resistant HMESO or PPM Mill cells with high endogenous levels of ERKs or AKT did not show dose-responsive increases in pERK1/ERK1, pERK2/ERK2, or pAKT/AKT levels by asbestos. However, small hairpin ERK2 stable cell lines created from both malignant mesothelioma lines were more sensitive to asbestos toxicity than shERK1 and shControl lines, and exhibited unique, tumor-specific changes in endogenous cell death - related gene expression. Our results suggest that EGFR phosphorylation is causally linkedto pERK and pAKT activation by asbestos in normal and SV40 Tag - immortalized human mesothelial cells. They also indicate that ERK2 plays a role in modulating asbestos toxicity by regulating genes critical to cell injury and survival that are differentially expressed in human mesotheliomas.

Treatment rationale study design for the MetLung trial : a randomized, double-blind phase III study of onartuzumab (MetMAb) in combination with erlotinib versus erlotinib alone in patients who have received standard chemotherapy for stage IIIB or IV met-positive non-small-cell lung cancer

We present the treatment rationale and study design of the MetLung phase III study. This study will investigate onartuzumab (MetMAb) in combination with erlotinib compared with erlotinib alone, as second- or third-line treatment, in patients with advanced non-small-cell lung cancer (NSCLC) who are Met-positive by immunohistochemistry. Approximately 490 patients (245 per treatment arm) will receive erlotinib (150 mg oral daily) plus onartuzumab or placebo (15 mg/kg intravenous every 3 weeks) until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. The efficacy objectives of this study are to compare overall survival (OS) (primary endpoint), progression-free survival, and response rates between the 2 treatment arms. In addition, safety, quality of life, pharmacokinetics, and translational research will be investigated across treatment arms. If the primary objective (OS) is achieved, this study will provide robust results toward an alternative treatment option for patients with Met-positive second- or third-line NSCLC. © 2012 Elsevier Inc. All Rights Reserved.

Mobile silencing in plants: what is the signal and what defines the target

RNA-mediated silencing in plants can spread from cell to cell and over a long distance, and such mobile silencing has been extensively studied in the past decade. However, major questions remain as to what is the exact nature of the mobile silencing signals, how the components of the RNA-directed DNA methylation pathway are involved, and why systemic spread of silencing has only been observed for transgenes but not endogenous genes. In this review, we provide an overview of the current knowledge on mobile gene silencing in plants and present a model where systemic silencing involves long nuclear RNA transcripts that serve as a template to amplify primary siRNA signals.

Effect of defects on fracture strength of graphene sheets

With a hexagonal monolayer network of carbon atoms, graphene has demonstrated exceptional electrical 22 and mechanical properties. In this work, the fracture of graphene sheets with Stone–Wales type defects and vacancies were investigated using molecular dynamics simulations at different temperatures. The initiation of defects via bond rotation was also investigated. The results indicate that the defects and vacancies can cause significant strength loss in graphene. The fracture strength of graphene is also affected by temperature and loading directions. The simulation results were compared with the prediction from the quantized fracture mechanics.

Development of a new signal processing diagnostic tool for vibration signals acquired in transient conditions

The diagnostics of mechanical components operating in transient conditions is still an open issue, in both research and industrial field. Indeed, the signal processing techniques developed to analyse stationary data are not applicable or are affected by a loss of effectiveness when applied to signal acquired in transient conditions. In this paper, a suitable and original signal processing tool (named EEMED), which can be used for mechanical component diagnostics in whatever operating condition and noise level, is developed exploiting some data-adaptive techniques such as Empirical Mode Decomposition (EMD), Minimum Entropy Deconvolution (MED) and the analytical approach of the Hilbert transform. The proposed tool is able to supply diagnostic information on the basis of experimental vibrations measured in transient conditions. The tool has been originally developed in order to detect localized faults on bearings installed in high speed train traction equipments and it is more effective to detect a fault in non-stationary conditions than signal processing tools based on spectral kurtosis or envelope analysis, which represent until now the landmark for bearings diagnostics.

Signal Processing Diagnostic Tool for Rolling Element Bearings Using EMD and MED

The signal processing techniques developed for the diagnostics of mechanical components operating in stationary conditions are often not applicable or are affected by a loss of effectiveness when applied to signals measured in transient conditions. In this chapter, an original signal processing tool is developed exploiting some data-adaptive techniques such as Empirical Mode Decomposition, Minimum Entropy Deconvolution and the analytical approach of the Hilbert transform. The tool has been developed to detect localized faults on bearings of traction systems of high speed trains and it is more effective to detect a fault in non-stationary conditions than signal processing tools based on envelope analysis or spectral kurtosis, which represent until now the landmark for bearings diagnostics.

Exploring the effect of aquatic exercise on behaviour and psychological wellbeing in people with moderate to severe dementia : a pilot study of the Watermemories Swimming Club

Aim To explore the effects of a dementia-specific, aquatic exercise intervention on behavioural and psychological symptoms in people with dementia (BPSD). Method Residents from two aged care facilities in Queensland, Australia, received a 12-week intervention consisting of aquatic exercises for strength, agility, flexibility, balance and relaxation. The Psychological Well-Being in Cognitively Impaired Persons Scale (PW-BCIP) and the Revised Memory and Behaviour Problems Checklist (RMBPC) were completed by registered nurses at baseline, week 6, week 9 and post intervention. Results Ten women and one man (median age = 88.4 years, interquartile range = 12.3) participated. Statistically significant declines in the RMBPC and PW-BCIP were observed over the study period. Conclusion Preliminary evidence suggests that a dementia-specific, aquatic exercise intervention reduces BPSD and improves psychological well-being in people with moderate to severe dementia. With further testing, this innovative intervention may prove effective in addressing some of the most challenging aspects of dementia care.

Small signal stability analysis of power systems with high penetration of wind power

The integration of large amount of wind power into a power system imposes a new challenge for the secure and economic operation of the system. It is necessary to investigate the impacts of wind power generation on the dynamic behavior of the power system concerned. This paper investigates the impacts of large amount of wind power on small signal stability and the corresponding control strategies to mitigate the negative effects. The concepts of different types of wind turbine generators (WTGs) and the principles of the grid-connected structures of wind power generation systems are first briefly introduced. Then, the state-of-the-art of the studies on the impacts of WTGs on small signal stability as well as potential problems to be studied are clarified. Finally, the control strategies on WTGs to enhance power system damping characteristics are presented.

Impacts of different wind power generators on power system small signal and transient stability

With the ever-increasing penetration level of wind power, the impacts of wind power on the power system are becoming more and more significant. Hence, it is necessary to systematically examine its impacts on the small signal stability and transient stability in order to find out countermeasures. As such, a comprehensive study is carried out to compare the dynamic performances of power system respectively with three widely-used power generators. First, the dynamic models are described for three types of wind power generators, i. e. the squirrel cage induction generator (SCIG), doubly fed induction generator (DFIG) and permanent magnet generator (PMG). Then, the impacts of these wind power generators on the small signal stability and transient stability are compared with that of a substituted synchronous generator (SG) in the WSCC three-machine nine-bus system by the eigenvalue analysis and dynamic time-domain simulations. Simulation results show that the impacts of different wind power generators are different under small and large disturbances.

The association of early life supplemental nutrition with lean body mass and grip strength in adulthood : evidence from APCAPS

In the present study, we examined the associations of early nutrition with adult lean body mass (LBM) and muscle strength in a birth cohort that was established to assess the long-term impact of a nutrition program. Participants (n = 1,446, 32% female) were born near Hyderabad, India, in 29 villages from 1987 to 1990, during which time only intervention villages (n = 15) had a government program that offered balanced protein-calorie supplementation to pregnant women and children. Participants’ LBM and appendicular skeletal muscle mass were measured using dual energy x-ray absorptiometry; grip strength and information on lifestyle indicators, including diet and physical activity level, were also obtained. Ages (mean = 20.3 years) and body mass indexes (weight (kg)/height (m)2; mean = 19.5) of participants in 2 groups were similar. Current dietary energy intake was higher in the intervention group. Unadjusted LBM and grip strength were similar in 2 groups. After adjustment for potential confounders, the intervention group had lower LBM (β = −0.75; P = 0.03), appendicular skeletal muscle mass, and grip strength than did controls, but these differences were small in magnitude (<0.1 standard deviation). Multivariable regression analyses showed that current socioeconomic position, energy intake, and physical activity level had a positive association with adult LBM and muscle strength. This study could not detect a “programming” effect of early nutrition supplementation on adult LBM and muscle strength.

Multidirectional effects of Sr, Mg and Si-containing bioceramic coatings with high bonding strength on inflammation, osteoclastogenesis and osteogenesis

Ideal coating materials for implants should be able to induce excellent osseointegration, which requires several important parameters, such as good bonding strength, limited inflammatory reaction, balanced osteoclastogenesis and osteogenesis, to gain well-functioning coated implants with long-term life span after implantation. Bioactive elements, like Sr, Mg and Si, have been found to play important roles in regulating the biological responses. It is of great interest to combine bioactive elements for developing bioactive coatings on Ti-6Al-4V orthopedic implants to elicit multidirectional effects on the osseointegration. In this study, Sr, Mg and Si-containing bioactive Sr2MgSi2O7 (SMS) ceramic coatings on Ti-6Al-4V were successfully prepared by plasma-spray coating method. The prepared SMS coatings have significantly higher bonding strength (~37MPa) than conventional pure hydroxyapatite (HA) coatings (mostly in the range of 15-25 MPa). It was also found that the prepared SMS coatings switch the macrophage phenotype into M2 extreme, inhibiting the inflammatory reaction via the inhibition of Wnt5A/Ca2+ and Toll-like receptor (TLR) pathways of macrophages. In addition, the osteoclastic activities were also inhibited by SMS coatings. The expression of osteoclastogenesis related genes (RANKL and MCSF) in bone marrow derived mesenchymal cells (BMSCs) with the involvement of macrophages was decreased, while OPG expression was enhanced on SMS coatings compared to HA coatings, indicating that SMS coatings also downregulated the osteoclastogenesis. However, the osteogenic differentiation of BMSCs with the involvement of macrophages was comparable between SMS and HA coatings. Therefore, the prepared SMS coatings showed multidirectional effects, such as improving bonding strength, reducing inflammatory reaction and downregulating osteoclastic activities, but maintaining a comparable osteogenesis, as compared with HA coatings. The combination of bioactive elements of Sr, Mg and Si into bioceramic coatings can be a promising method to develop bioactive implants with multifunctional properties for orthopaedic application.

Characterising an ECG signal using statistical modelling : a feasibility study

For clinical use, in electrocardiogram (ECG) signal analysis it is important to detect not only the centre of the P wave, the QRS complex and the T wave, but also the time intervals, such as the ST segment. Much research focused entirely on qrs complex detection, via methods such as wavelet transforms, spline fitting and neural networks. However, drawbacks include the false classification of a severe noise spike as a QRS complex, possibly requiring manual editing, or the omission of information contained in other regions of the ECG signal. While some attempts were made to develop algorithms to detect additional signal characteristics, such as P and T waves, the reported success rates are subject to change from person-to-person and beat-to-beat. To address this variability we propose the use of Markov-chain Monte Carlo statistical modelling to extract the key features of an ECG signal and we report on a feasibility study to investigate the utility of the approach. The modelling approach is examined with reference to a realistic computer generated ECG signal, where details such as wave morphology and noise levels are variable.

Understanding the abnormal brain activity in epilepsy as a potential predictor of the onset of an epileptic seizure

The Brain Research Institute (BRI) uses various types of indirect measurements, including EEG and fMRI, to understand and assess brain activity and function. As well as the recovery of generic information about brain function, research also focuses on the utilisation of such data and understanding to study the initiation, dynamics, spread and suppression of epileptic seizures. To assist with the future focussing of this aspect of their research, the BRI asked the MISG 2010 participants to examine how the available EEG and fMRI data and current knowledge about epilepsy should be analysed and interpreted to yield an enhanced understanding about brain activity occurring before, at commencement of, during, and after a seizure. Though the deliberations of the study group were wide ranging in terms of the related matters considered and discussed, considerable progress was made with the following three aspects. (1) The science behind brain activity investigations depends crucially on the quality of the analysis and interpretation of, as well as the recovery of information from, EEG and fMRI measurements. A number of specific methodologies were discussed and formalised, including independent component analysis, principal component analysis, profile monitoring and change point analysis (hidden Markov modelling, time series analysis, discontinuity identification). (2) Even though EEG measurements accurately and very sensitively record the onset of an epileptic event or seizure, they are, from the perspective of understanding the internal initiation and localisation, of limited utility. They only record neuronal activity in the cortical (surface layer) neurons of the brain, which is a direct reflection of the type of electrical activity they have been designed to record. 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