Integrin αvβ3 mediates upregulation of epidermal growth-factor receptor expression and activity in human ovarian cancer cells

Upon overexpression of integrin αvβ3 and its engagement by vitronectin, we previously showed enhanced adhesion, proliferation, and motility of human ovarian cancer cells. By studying differential expression of genes possibly related to these tumor biological events, we identified the epidermal growth-factor receptor (EGF-R) to be under control of αvβ3 expression levels. Thus in the present study we characterized αvβ3-dependent changes of EGF-R and found significant upregulation of its expression and activity which was reflected by prominent changes of EGF-R promoter activity. Upon disruption of DNA-binding motifs for the transcription factors p53, ETF, the repressor ETR, p50, and c-rel, respectively, we sought to identify DNA elements contributing to αvβ3-mediated EGF-R promoter induction. Both, the p53- and ETF-mutant, while exhibiting considerably lower EGF-R promoter activity than the wild type promoter, retained inducibility by αvβ3. Mutation of the repressor motif ETR, as expected, enhanced EGF-R promoter activity with a further moderate increase upon αvβ3 elevation. The p50-mutant displayed EGF-R promoter activity almost comparable to that of the wild type promoter with no impairment of induction by αvβ3. However, the activity of an EGF-R promoter mutant displaying a disrupted c-rel-binding motif did not only prominently decline, but, moreover, was not longer responsive to enhanced αvβ3, involving this DNA element in αvβ3-dependent EGF-R upregulation. Moreover, αvβ3 did not only increase the EGF-R but, moreover, also led to obvious co-clustering on the cancer cell surface. By studying αvβ3/EGF-R-effects on the focal adhesion kinase (FAK) and the mitogen activated protein kinases (MAPK) p44/42 (erk−1/erk−2), having important functions in synergistic crosstalk between integrins and growth-factor receptors, we found for both significant enhancement of expression and activity upon αvβ3/VN interaction and cell stimulation by EGF. Upregulation of the EGF-R by integrin αvβ3, both receptor molecules with a well-defined role as targets for cancer treatment, might represent an additional mechanism to adapt synergistic receptor signaling and crosstalk in response to an altered tumor cell microenvironment during ovarian cancer progression.

Factor Five : Transforming the Global Economy through 80% Improvements in Resource Productivity

The 21st century will see monumental change. Either the human race will use its knowledge and skills and change the way it interacts with the environment, or the environment will change the way it interacts with its inhabitants. In the first case, the focus of this book, we would see our sophisticated understanding in areas such as physics, chemistry, engineering, biology, planning, commerce, business and governance accumulated over the last 1,000 years brought to bear on the challenge of dramatically reducing our pressure on the environment. The second case however is the opposite scenario, involving the decline of the planet’s ecosystems until they reach thresholds where recovery is not possible, and following which we have no idea what happens. For instance, if we fail to respond to Sir Nicolas Stern’s call to meet appropriate stabilisation trajectories for greenhouse gas emissions, and we allow the average temperature of our planets surface to increase by 4-6 degrees Celsius, we will see staggering changes to our environment, including rapidly rising sea level, withering crops, diminishing water reserves, drought, cyclones, floods… allowing this to happen will be the failure of our species, and those that survive will have a deadly legacy. In this update to the 1997 International Best Seller, Factor Four, Ernst von Weizsäcker again leads a team to present a compelling case for sector wide advances that can deliver significant resource productivity improvements over the coming century. The purpose of this book is to inspire hope and to then inform meaningful action in the coming decades to respond to the greatest challenge our species has ever faced – that of living in harmony with our planet and its other inhabitants.

Challenges for implementation of a new model of collaborative design management: Analyzing the impact of human factor

The ineffectiveness of current design processes has been well studied and has resulted in widespread calls for the evolution and development of new management processes. Even following the advent of BIM, we continue to move from one stage to another without necessarily having resolved all the issues. CAD design technology, if well handled, could have significantly raised the level of quality and efficiency of current processes, but in practice this was not fully realized. Therefore, technology alone can´t solve all the problems and the advent of BIM could result in a similar bottleneck. For a precise definition of the problem to be solved we should start by understanding what are the main current bottlenecks that have yet to be overcome by either new technologies or management processes, and the impact of human behaviour-related issues which impact the adoption and utilization of new technologies. The fragmented and dispersed nature of the AEC sector, and the huge number of small organizations that comprise it, are a major limiting factor. Several authors have addressed this issue and more recently IDDS has been defined as the highest level of achievement. However, what is written on IDDS shows an extremely ideal situation on a state to be achieved; it shows a holistic utopian proposition with the intent to create the research agenda to move towards that state. Key to IDDS is the framing of a new management model which should address the problems associated with key aspects: technology, processes, policies and people. One of the primary areas to be further studied is the process of collaborative work and understanding, together with the development of proposals to overcome the many cultural barriers that currently exist and impede the advance of new management methods. The purpose of this paper is to define and delimit problems to be solved so that it is possible to implement a new management model for a collaborative design process.

Assessment of gene expression of intracellular calcium channels, pumps and exchangers with epidermal growth factor-induced epithelial-mesenchymal transition in a breast cancer cell line

Background Epithelial-mesenchymal transition (EMT) is a process implicated in cancer metastasis that involves the conversion of epithelial cells to a more mesenchymal and invasive cell phenotype. In breast cancer cells EMT is associated with altered store-operated calcium influx and changes in calcium signalling mediated by activation of cell surface purinergic receptors. In this study, we investigated whether MDA-MB-468 breast cancer cells induced to undergo EMT exhibit changes in mRNA levels of calcium channels, pumps and exchangers located on intracellular calcium storing organelles, including the Golgi, mitochondria and endoplasmic reticulum (ER). Methods Epidermal growth factor (EGF) was used to induce EMT in MDA-MB-468 breast cancer cells. Serum-deprived cells were treated with EGF (50 ng/mL) for 12 h and gene expression was assessed using quantitative RT-PCR. Results and conclusions These data reveal no significant alterations in mRNA levels of the Golgi calcium pump secretory pathway calcium ATPases (SPCA1 and SPCA2), or the mitochondrial calcium uniporter (MCU) or Na+/Ca2+ exchanger (NCLX). However, EGF-induced EMT was associated with significant alterations in mRNA levels of specific ER calcium channels and pumps, including (sarco)-endoplasmic reticulum calcium ATPases (SERCAs), and inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RYR) calcium channel isoforms. The most prominent change in gene expression between the epithelial and mesenchymal-like states was RYR2, which was enriched 45-fold in EGF-treated MDA-MB-468 cells. These findings indicate that EGF-induced EMT in breast cancer cells may be associated with major alterations in ER calcium homeostasis.

Neutrophil gelatinase-associated lipocalin (NGAL) an early-screening biomarker for ovarian cancer : NGAL is associated with epidermal growth factor-induced epithelio-mesenchymal transition

The expression of neutrophil gelatinase-associated lipocalin (NGAL) has been shown to be upregulated in ovarian cancer cells. In this study, we report that the expression of immunoreactive NGAL (irNGAL) in ovarian tumors changes with disease grade and that this change is reflected in the concentration of NGAL in peripheral blood. A total of 59 ovarian tissues including normal, benign, borderline malignant and grades 1, 2 and 3 malignant were analyzed using immunohistochemistry. irNGAL was not present in normal ovaries and the NGAL expression was weak to moderate in benign tissues. Both borderline and grade 1 tumors displayed the highest amount of NGAL expression with moderate to strong staining, whereas in grade 2 and 3 tumors, the extent of staining was significantly less (p < 0.01) and staining intensity was weak to moderate. Staining in all cases was confined to the epithelium. NGAL expression was analyzed by ELISA in 62 serum specimens from normal and different grades of cancer patients. Compared to control samples, the NGAL concentration was 2 and 2.6-fold higher in the serum of patients with benign tumors and cancer patients with grade 1 tumors (p < 0.05) and that result was consistent with the expression of NGAL performed by Western blot. NGAL expression was evaluated by Western blot in an immortalized normal ovarian cell line (IOSE29) as well as ovarian cancer cell lines. Moderate to strong expression of NGAL was observed in epithelial ovarian cancer cell lines SKOV3 and OVCA433 while no expression of NGAL was evident in normal IOSE29 and mesenchyme-like OVHS1, PEO.36 and HEY cell lines. NGAL expression was downregulated in ovarian cancer cell lines undergoing epithelio-mesenchymal transition (EMT) induced by epidermal growth factor (EGF). Down-regulation of NGAL expression correlated with the upregulation of vimentin expression, enhanced cell dispersion and downregulation of E-cadherin expression, some of the hallmarks of EMT. EGF-induced EMT phenotypes were inhibited in the presence of AG1478, an inhibitor of EGF receptor tyrosine kinase activity. These data indicate that NGAL may be a good marker to monitor changes of benign to premalignant and malignant ovarian tumors and that the molecule may be involved in the progression of epithelial ovarian malignancies.

Total factor productivity growth and convergence in the petroleum industry : empirical analysis testing for convexity

While economic theory acknowledges that some features of technology (e.g., indivisibilities, economies of scale and specialization) can fundamentally violate the traditional convexity assumption, almost all empirical studies accept the convexity property on faith. In this contribution, we apply two alternative flexible production technologies to measure total factor productivity growth and test the significance of the convexity axiom using a nonparametric test of closeness between unknown distributions. Based on unique field level data on the petroleum industry, the empirical results reveal significant differences, indicating that this production technology is most likely non-convex. Furthermore, we also show the impact of convexity on answers to traditional convergence questions in the productivity growth literature.

Co-movements in commodity prices : a note based on network analysis

This article analyses co-movements in a wide group of commodity prices during the time period 1992–2010. Our methodological approach is based on the correlation matrix and the networks inside. Through this approach we are able to summarize global interaction and interdependence, capturing the existing heterogeneity in the degrees of synchronization between commodity prices. Our results produce two main findings: (a) we do not observe a persistent increase in the degree of co-movement of the commodity prices in our time sample, however from mid-2008 to the end of 2009 co-movements almost doubled when compared with the average correlation; (b) we observe three groups of commodities which have exhibited similar price dynamics (metals, oil and grains, and oilseeds) and which have increased their degree of co-movement during the sampled period.

Moderate physical activity level as a protective factor against metabolic syndrome in middle-aged and older women

Aims and objectives To investigate whether physical activity is a protective factor against metabolic syndrome in middle-aged and older women. Background Socio-demographic and lifestyle behaviour factors contribute to metabolic syndrome. To minimise the risk of metabolic syndrome, several global guidelines recommend increasing physical activity level. However, only limited research has investigated the relationship between physical activity levels and metabolic syndrome in middle-aged and older women after adjusting for socio-demographic and lifestyle behaviour factors. Design Cross-sectional design. Methods A convenience sample of 326 middle-aged and older women was recruited. Metabolic syndrome was confirmed according to the National Cholesterol Education Program, Adult Treatment Panel III guidelines, and physical activity levels were measured by the International Physical Activity Questionnaire. Results The sample had a mean age of 60•9 years, and the prevalence of metabolic syndrome was 43•3%. Postmenopausal women and women with low socioeconomic status (low-education background, without personal income and currently unemployed) had a significantly higher risk of developing metabolic syndrome. After adjusting for significant socio-demographic and lifestyle behaviour factors, the women with moderate or high physical activity levels had a significantly lower (OR = 0•10; OR = 0•11, p < 0•001) risk of metabolic syndrome and a lower risk for each specific component of metabolic syndrome, including elevated fasting plasma glucose (OR = 0•29; OR = 0•26, p = 0•009), elevated blood pressure (OR = 0•18; OR = 0•32, p = 0•029), elevated triglycerides (OR = 0•41; OR = 0•15, p = 0•001), reduced high-density lipoprotein (OR = 0•28; OR = 0•27, p = 0•004) and central obesity (OR = 0•31; OR = 0•22, p = 0•027). Conclusions After adjusting for socio-demographic and lifestyle behaviour factors, physical activity level was a significant protective factor against metabolic syndrome in middle-aged and older women. Higher physical activity levels (moderate or high physical activity level) reduced the risk of metabolic syndrome in middle-aged and older women. Relevance to clinical practice Appropriate strategies should be developed to encourage middle-aged and older women across different socio-demographic backgrounds to engage in moderate or high levels of physical activity to reduce the risk of metabolic syndrome.

Re-examining habitual residence as the sole connecting factor in Hague Convention child abduction cases

This article critiques the usefulness of habitual residence as the sole connecting factor in Hague Convention child abduction cases. This is achieved by examining the quality of this jurisdiction in light of changes in the gender dynamics underpinning international parental child abduction and the transnational family phenomenon. Arguably, the child’s habitual residence as a home environment of the nature anticipated by the Convention’s drafters is an increasingly outdated construct. This is due to an increase in both the number of abducting primary-carer mothers, and their families’ growing mobility. Judicial determinations of habitual residence made during Conven- tion return proceedings are entrenched in the state-centric paradigm. This paradigm is becoming increasingly incompatible with the lives of families which experience international parental child abduction.

Inventory of pedagogy and practice: Confirmatory factor analysis of multiple facets of teaching

Student perceptions of teaching have often been used in tertiary education for evaluation purposes. However, there is a paucity of research on the validity, reliability, and applicability of instruments that cover a wide range of student perceptions of pedagogies and practices in high school settings for descriptive purposes. The study attempts to validate an inventory of pedagogy and practice (IPP) that provides researchers and practitioners with a psychometrically sound instrument that covers the most salient factors related to teaching. Using a sample of students (N = 1515) from 39 schools in Singapore, 14 factors about teaching in English lessons from the students’ perspective were tested with confirmatory factor analysis (classroom task goal, structure and clarity, curiosity and interest, positive class climate, feedback, questioning, quality homework, review of students’ work, conventional teaching, exam preparation, behaviour management, maximizing learning time, student-centred pedagogy, and subject domain teaching). Two external criterion factors were used to further test the IPP factor structure. The inventory will enable teachers to understand more about their teaching and researchers to examine how teaching may be related to learning outcomes.

SME international performance in Latin America: The role of entrepreneurial and technological capabilities

SMEs from emerging markets in Latin America are increasingly engaging in internationalization. Nevertheless, there is limited research into how these firms achieve international performance. This study proposes and tests a conceptual model that considers managerial and technology-related capabilities and their impact on international performance of SMEs. The model uses confirmatory factor analysis (CFA) to develop the underlying multi-item constructs and structural equation modeling (SEM) to test the model with data from 233 Chilean SMEs. Specifically, the model considers the role of international entrepreneurial orientation and Internet capabilities on international market performance, taking into account the mediating effect of international entrepreneurial opportunity recognition and technology-related international networks. Results show that international entrepreneurial opportunity recognition and international networks mediate the relationship between international entrepreneurial orientation and Internet marketing capabilities on SME international performance.

First-Line afatinib versus chemotherapy in patients with non–small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases

Introduction Metastatic spread to the brain is common in patients with non–small cell lung cancer (NSCLC), but these patients are generally excluded from prospective clinical trials. The studies, phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations (LUX-Lung 3) and a randomized, open-label, phase III study of BIBW 2992 versus chemotherapy as first-line treatment for patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation (LUX-Lung 6) investigated first-line afatinib versus platinum-based chemotherapy in epidermal growth factor receptor gene (EGFR) mutation-positive patients with NSCLC and included patients with brain metastases; prespecified subgroup analyses are assessed in this article. Methods For both LUX-Lung 3 and LUX-Lung 6, prespecified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n = 35 and n = 46, respectively). Post hoc analyses of clinical outcomes was undertaken in the combined data set (n = 81). Results In both studies, there was a trend toward improved PFS with afatinib versus chemotherapy in patients with brain metastases (LUX-Lung 3: 11.1 versus 5.4 months, hazard ratio [HR] = 0.54, p = 0.1378; LUX-Lung 6: 8.2 versus 4.7 months, HR = 0.47, p = 0.1060). The magnitude of PFS improvement with afatinib was similar to that observed in patients without brain metastases. In combined analysis, PFS was significantly improved with afatinib versus with chemotherapy in patients with brain metastases (8.2 versus 5.4 months; HR, 0.50; p = 0.0297). Afatinib significantly improved the objective response rate versus chemotherapy in patients with brain metastases. Safety findings were consistent with previous reports. Conclusions These findings lend support to the clinical activity of afatinib in EGFR mutation–positive patients with NSCLC and asymptomatic brain metastases.