Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: Results of an open-label, randomized, controlled phase II study (CERTO)

Background: This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. Results: There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvβ3 and αvβ5 expression was neither a predictive nor a prognostic indicator. Conclusions: The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment.

VEGF-mediated cell survival in non-small-cell lung cancer: implications for epigenetic targeting of VEGF receptors as a therapeutic approach

Aims: To evaluate the potential therapeutic utility of histone deacetylase inhibitors (HDACi) in targeting VEGF receptors in non-small-cell lung cancer. Materials & methods: Non-small-cell lung cancer cells were screened for the VEGF receptors at the mRNA and protein levels, while cellular responses to various HDACi were examined. Results: Significant effects on the regulation of the VEGF receptors were observed in response to HDACi. These were associated with decreased secretion of VEGF, decreased cellular proliferation and increased apoptosis which could not be rescued by addition of exogenous recombinant VEGF. Direct remodeling of the VEGFR1 and VEGFR2 promoters was observed. In contrast, HDACi treatments resulted in significant downregulation of the Neuropilin receptors. Conclusion: Epigenetic targeting of the Neuropilin receptors may offer an effective treatment for lung cancer patients in the clinical setting.

Mutational analysis of the insulin‑like growth factor 1 receptor tyrosine kinase domain in non-small cell lung cancer patients

The insulin‑like growth factor 1 receptor (IGF1R) pathway plays an important role in the pathogenesis of non‑small cell lung cancer (NSCLC) and also provides a mechanism of resistance to targeted therapies. IGF1R is therefore an ideal therapeutic target and several inhibitors have entered clinical trials. However, thus far the response to these inhibitors has been poor, highlighting the importance of predictive biomarkers to identify patient cohorts who will benefit from these targeted agents. It is well‑documented that mutations and/or deletions in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain predict sensitivity of NSCLC patients to EGFR TK inhibitors. Single‑nucleotide polymorphisms (SNPs) in the IGF pathway have been associated with disease, including breast and prostate cancer. The aim of the present study was to elucidate whether the IGF1R TK domain harbours SNPs, somatic mutations or deletions in NSCLC patients and correlates the mutation status to patient clinicopathological data and prognosis. Initially 100 NSCLC patients were screened for mutations/deletions in the IGF1R TK domain (exons 16‑21) by sequencing analysis. Following the identification of SNP rs2229765, a further 98 NSCLC patients and 866 healthy disease‑free control patients were genotyped using an SNP assay. The synonymous SNP (rs2229765) was the only aberrant base change identified in the IGF1R TK domain of 100 NSCLC patients initially analysed. SNP rs2229765 was detected in exon 16 and was found to have no significant association between IGF1R expression and survival. The GA genotype was identified in 53.5 and 49.4% of NSCLC patients and control individuals, respectively. No significant difference was found in the genotype (P=0.5487) or allele (P=0.9082) frequencies between the case and control group. The present findings indicate that in contrast to the EGFR TK domain, the IGF1R TK domain is not frequently mutated in NSCLC patients. The synonymous SNP (rs2229765) had no significant association between IGF1R expression and survival in the cohort of NSCLC patients.

2nd ESMO Consensus Conference in Lung Cancer: Locally advanced stage III non-small-cell lung cancer

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11–12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on locally advanced disease.

Microarchitecture sensitive empirical models for compiler optimizations.

This paper proposes the use of empirical modeling techniques for building microarchitecture sensitive models for compiler optimizations. The models we build relate program performance to settings of compiler optimization flags, associated heuristics and key microarchitectural parameters. Unlike traditional analytical modeling methods, this relationship is learned entirely from data obtained by measuring performance at a small number of carefully selected compiler/microarchitecture configurations. We evaluate three different learning techniques in this context viz. linear regression, adaptive regression splines and radial basis function networks. We use the generated models to a) predict program performance at arbitrary compiler/microarchitecture configurations, b) quantify the significance of complex interactions between optimizations and the microarchitecture, and c) efficiently search for'optimal' settings of optimization flags and heuristics for any given microarchitectural configuration. Our evaluation using benchmarks from the SPEC CPU2000 suits suggests that accurate models (< 5% average error in prediction) can be generated using a reasonable number of simulations. We also find that using compiler settings prescribed by a model-based search can improve program performance by as much as 19% (with an average of 9.5%) over highly optimized binaries.

Small-angle x-ray scattering study of the aggregation of gold nanoparticles during formation at the toluene-water interface

We report the results of an in situ small-angle x-ray scattering (SAXS) study of the aggregation of gold nanoparticles formed by an interfacial reaction at the toluene-water interface. The SAXS data provide a direct evidence for aggregate formation of nanoparticles having 1.3 nm gold core and an organic shell that gives a core-core separation of about 2.5 nm. Furthermore, the nanoparticles do not occupy all the cites of 13-member cluster. This occupancy decreases with reaction time and indicate reorganization of the clusters that generates planner disklike structures. A gradual increase in fractal dimension from 1.82 to 2.05 also indicate compactification of cluster aggregation with reaction time, the final exponent being close to 2 expected for disklike aggregates.

ACE Research Vignette 051: How and Why is Small Business Managers’ Age Related To Business Growth?

This series of research vignettes is aimed at sharing current and interesting research findings from our team of international entrepreneurship researchers. This vignette, written by Professor Hannes Zacher, Professor Michael M. Gielnik and Dr Antje Schmitt, reports findings on relationships between small business managers’ age, their focus on opportunities, and business growth (sales and number of employees) over five years.

ACE Research Vignette #52: Business growth and new initiatives in small and medium manufacturing enterprises from a design innovation program

This series of research vignettes is aimed at sharing current and interesting research findings from our team of international Entrepreneurship researchers. This vignette, written by Dr Judy Matthews examines the effects of firm engagement with design innovation programs on entrepreneurial activities of small and medium enterprises.

Unusual RNA plant virus integration in the soybean genome leads to the production of small RNAs

Horizontal gene transfer (HGT) is known to be a major force in genome evolution. The acquisition of genes from viruses by eukaryotic genomes is a well-studied example of HGT, including rare cases of non-retroviral RNA virus integration. The present study describes the integration of cucumber mosaic virus RNA-1 into soybean genome. After an initial metatranscriptomic analysis of small RNAs derived from soybean, the de novo assembly resulted a 3029-nt contig homologous to RNA-1. The integration of this sequence in the soybean genome was confirmed by DNA deep sequencing. The locus where the integration occurred harbors the full RNA-1 sequence followed by the partial sequence of an endogenous mRNA and another sequence of RNA-1 as an inverted repeat and allowing the formation of a hairpin structure. This region recombined into a retrotransposon located inside an exon of a soybean gene. The nucleotide similarity of the integrated sequence compared to other Cucumber mosaic virus sequences indicates that the integration event occurred recently. We described a rare event of non-retroviral RNA virus integration in soybean that leads to the production of a double-stranded RNA in a similar fashion to virus resistance RNAi plants.

The emerging world of small ORFs

Small open reading frames (sORFs) are an often overlooked feature of plant genomes. Initially found in plant viral RNAs and considered an interesting curiosity, an increasing number of these sORFs have been shown to encode functional peptides or play a regulatory role. The recent discovery that many of these sORFs initiate with start codons other than AUG, together with the identification of functional small peptides encoded in supposedly noncoding primary miRNA transcripts (pri-miRs), has drastically increased the number of potentially functional sORFs within the genome. Here we review how advances in technology, notably ribosome profiling (RP) assays, are complementing bioinformatics and proteogenomic methods to provide powerful ways to identify these elusive features of plant genomes, and highlight the regulatory roles sORFs can play.

How small business managers’ age and focus on opportunities affect business growth: A mediated moderation growth model

Research on business growth has been criticized for methodological weaknesses. We present a mediated moderation growth model as a new methodological approach. We hypothesized that small business managers' age negatively affects business growth through focus on opportunities. We sampled 201 small business managers and obtained firm performance data over 5 years, resulting in 836 observations. Growth modeling showed systematic differences in firm performance trajectories. These differences could be explained by modeling focus on opportunities as a mediator of the relationship between small business managers' age and business growth. The study illustrates how mediation models can be tested using growth modeling.

Water in Action : Encounters among 2- to 3-Year-Old Children, Adults, and Water in Day Care

In line with cultural psychology and developmental theory, a single case approach is applied to construct knowledge on how children s interaction emerge interlinked to historical, social, cultural, and material context. The study focuses on the negotiation of constraints and meaning construction among 2-to 3-year-old children, a preschool teacher, and the researcher in settings with water. Water as an element offers a special case of cultural canalization: adults selectively monitor and guide children s access to it. The work follows the socio-cultural tradition in psychology, particularly the co-constructivist theory of human development and the Network of Meanings perspective developed at the University of São Paulo. Valsiner s concepts of Zone of Free Movement and Zone of Promoted Action are applied together with studies where interactions are seen as spaces of construction where negotiation of constraints for actions, emotions, and conceptions occur. The corpus was derived at a Finnish municipal day care centre. During a seven months period, children s actions were video recorded in small groups twice a month. The teacher and the researcher were present. Four sessions with two children were chosen for qualitative microanalysis; the analysis also addressed the transformations during the months covered by the study. Moreover, the data derivation was analyzed reflectively. The narrowed down arenas for actions were continuously negotiated among the participants both nonverbally and verbally. The adults expectations and intentions were materialized in the arrangements of the setting canalizing the possibilities for actions. Children s co-regulated actions emerged in relation to the adults presence, re-structuring attempts, and the constraints of the setting. Children co-constructed novel movements and meanings in relation to the initiatives and objects offered. Gestures, postures, and verbalizations emerged from the initially random movements and became constructed to have specific meanings and functions; meaning construction became abbreviated. The participants attempted to make sense of the ambiguous (explicit and implicit) intentions and fuzzy boundaries of promoted and possible actions: individualized yet overlapping features were continuously negotiated by all the participants. Throughout the months, children s actions increasingly corresponded adults (re-defined) conceptions of water researchers as an emerging group culture. Water became an instrument and a context for co-regulations. The study contributes to discussions on children as participants in cultural canalization and emphasizes the need for analysis in early childhood education practices on the implicit and explicit constraint structures for actions.