CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance

The use of taxanes has for decades been crucial for treatment of several cancers. A major limitation of these therapies is inherent or acquired drug resistance. A key to improved outcome of taxane-based therapies is to develop tools to predict and monitor drug efficacy and resistance in the clinical setting allowing for treatment and dose stratification for individual patients. To assess treatment efficacy up to the level of drug target engagement, we have established several formats of tubulin-specific Cellular Thermal Shift Assays (CETSAs). This technique was evaluated in breast and prostate cancer models and in a cohort of breast cancer patients. Here we show that taxanes induce significant CETSA shifts in cell lines as well as in animal models including patient-derived xenograft (PDX) models. Furthermore, isothermal dose response CETSA measurements allowed for drugs to be rapidly ranked according to their reported potency. Using multidrug resistant cancer cell lines and taxane-resistant PDX models we demonstrate that CETSA can identify taxane resistance up to the level of target engagement. An imaging-based CETSA format was also established, which in principle allows for taxane target engagement to be accessed in specific cell types in complex cell mixtures. Using a highly sensitive implementation of CETSA, we measured target engagement in fine needle aspirates from breast cancer patients, revealing a range of different sensitivities. Together, our data support that CETSA is a robust tool for assessing taxane target engagement in preclinical models and clinical material and therefore should be evaluated as a prognostic tool during taxane-based therapies

Productivity in China's high technology industry:regional heterogeneity and R&D

This paper analyzes the impact of Research and Development (R&D) on the productivity of China's high technology industry. In order to capture important differences in the effect of R&D on output that arise from geographic and socioeconomic differences across three major regions in China, we use a novel semiparametric approach that allows us to model heterogeneities across provinces and time. Using a unique provincial level panel dataset spanning the period 2000–2007, we find that the impact of R&D on output varies substantially in terms of magnitude and significance across different regions. Results show that the eastern region benefits the most from R&D investments, however it benefits the least from technical progress, while the western region benefits the least from R&D investments, but enjoys the highest benefits from technical progress. The central region benefits from R&D investments more than the western region and benefits from technical progress more than the eastern region. Our results suggest that R&D investments would significantly increase output in both the eastern and central regions, however technical progress in the central region may further compound the effects of R&D on output within the region

The link between R&D, innovation and productivity: Are micro firms different?

We analyze the link between R&D, innovation, and productivity in MSMEs with a special focus on micro firms with fewer than 10 employees; usually constituting the majority of firms in industrialized economies. Using the German KfW SME panel, we examine to what extent micro firms are different from other firms in terms of innovativeness. We find that while firms engage in innovative activities with smaller probability, the smaller they are, for those firms that do make such investment, R&D intensity is larger the smaller firms are. For all MSMEs, the predicted R&D intensity is positively correlated with the probability of reporting innovation, with a larger effect size for product than for process innovations. Moreover, micro firms benefit in a comparable way from innovation processes as larger firms, as they are similarly able to increase their labor productivity. Overall, the link between R&D, innovation, and productivity in micro firms does not largely differ from their larger counterparts

Multi-objective optimization for optimum tolerance synthesis with process and machine selection using a genetic algorithm

This paper presents a new approach to the tolerance synthesis of the component parts of assemblies by simultaneously optimizing three manufacturing parameters: manufacturing cost, including tolerance cost and quality loss cost; machining time; and machine overhead/idle time cost. A methodology has been developed using the Genetic Algorithm (GA) technique to solve this multi-objective optimization problem. The effectiveness of the proposed methodology has been demonstrated by solving a wheel mounting assembly problem consisting of five components, two subassemblies, two critical dimensions, two functional tolerances, and eight operations. Significant cost saving can be achieved by employing this methodology

Direct Observations of Oxygen-induced Platinum Nanoparticle Ripening Studied by In Situ TEM

This study addresses the sintering mechanism of Pt nanoparticles dispersed on a planar, amorphous Al2O3 support as a model system for a catalyst for automotive exhaust abatement. By means of in situ transmission electron microscopy (TEM), the model catalyst was monitored during the exposure to 10 mbar air at 650 degrees C. Time-resolved image series unequivocally reveal that the sintering of Pt nanoparticles was mediated by an Ostwald ripening process. A statistical analysis of an ensemble of Pt nanoparticles shows that the particle size distributions change shape from an initial Gaussian distribution via a log-normal distribution to a Lifshitz-Slyozov-Wagner (LSW) distribution. Furthermore, the time-dependency of the ensemble-averaged particle size and particle density is determined. A mean field kinetic description captures the main trends in the observed behavior. However, at the individual nanoparticle level, deviations from the model are observed suggesting in part that the local environment influences the atom exchange process

A spill over effect of entrepreneurial orientation on technological innovativeness:an outlook of universities and research based spin offs

partially_open5siBy shifting towards Romer’s (Am Econ Rev 94:1002–1037, 1986) economy and so the spread of knowledge economy, universities started to adopt a collaborative approach with their entrepreneurial ecosystem. They turn out to be risk taker, autonomous, proactive, competitive, and innovative. In a nutshell, they are entrepreneurial oriented with the aim to generate new innovative ventures, known as research-based spin offs. Doubly, this has induced an improvement of technology transfer and the degree of entrepreneurship in the current knowledge economy. However there still is a paucity of studies on the spill over effect of entrepreneurial orientated universities and research-based spin off on technology transfer need to be more explored. Therefore, the article investigates the link between entrepreneurial orientation and such spill overs by offering an outlook of two universities and two research-based spin offs in the United Kingdom. The scope is to provide a deep view of technological innovativeness in a research context, entrepreneurial oriented. Our research suggests that entrepreneurial attitude has become an imperative to succeed in the context where British institutions currently operate. Entrepreneurship brings the necessary technological innovation to the university and its students, which results in better positioning of the university at national and international levels, with the subsequent impact on their ability to attract not only new students and academics but also funding to conduct their research.openScuotto, Veronica; Del Giudice, Manlio; Garcia-Perez, Alexeis; Orlando, Beatrice; Ciampi, FrancescoScuotto, Veronica; Del Giudice, Manlio; Garcia-Perez, Alexeis; Orlando, Beatrice; Ciampi, Francesc