Cell death triggered by alpha-emitting ²¹³Bi-immunoconjugates in HSC45-M2 gastric cancer cells is different from apoptotic cell death.

PURPOSE: Radioimmunotherapy with alpha-particle-emitting nuclides, such as 213Bi, is a promising concept for the elimination of small tumour nodules or single disseminated tumour cells. The aim of this study was to investigate cellular damage and the mode of cell death triggered by 213Bi-immunoconjugates. METHODS: Human gastric cancer cells (HSC45-M2) expressing d9-E-cadherin were incubated with different levels of activity of 213Bi-d9MAb targeting d9-E-cadherin and 213Bi-d8MAb, which does not bind to d9-E-cadherin. Micronucleated (M) cells, abnormal (A) cells and apoptotic (A) [(MAA)] cells were scored microscopically in the MAA assay following fluorescent staining of nuclei and cytoplasm. Chromosomal aberrations were analysed microscopically following Giemsa staining. The effect of z-VAD-fmk, known to inhibit apoptosis, on the prevention of cell death was investigated following treatment of HSC45-M2 cells with sorbitol as well as 213Bi-d9MAb. Activation of caspase 3 after incubation of HSC45-M2 cells with both sorbitol and 213Bi-d9MAb was analysed via Western blotting. RESULTS: Following incubation of HSC45-M2 human gastric cancer cells expressing d9-E-cadherin with 213Bi-d9MAb the number of cells killed increased proportional to the applied activity concentration. Microscopically visible effects of alpha-irradiation of HSC45-M2 cells were formation of micronuclei and severe chromosomal aberrations. Preferential induction of these lesions with specific 213Bi-d9MAb compared with unspecific 213Bi-d8MAb (not targeting d9-E-cadherin) was not observed if the number of floating, i.e. unbound 213Bi-immunoconjugates per cell exceeded 2 x 10(4), most likely due to intense crossfire. In contrast to sorbitol-induced cell death, cell death triggered by 213Bi-immunoconjugates was independent of caspase 3 activation and could not be inhibited by z-VAD-fmk, known to suppress the apoptotic pathway. CONCLUSION: 213Bi-immunoconjugates seem to induce a mode of cell death different from apoptosis in HSC45-M2 cells. &nbsp

Goal-Oriented Approach to Enable New Business Models for SME Using Smart Products

Part 2: Collaborative Environments and New Product DevelopmentInternational audienceThe manufacturing industry has to exploit trends like “Industrie 4.0” and digitization not only to design production more efficiently, but also to create and develop new and innovative business models [1, p. 2]. New business models ensure that even SMEs are able to open up new markets and canvass new customers [2, p. 82ff.]. This means that in order to stay competitive, SMEs must transform their existing business models [3, p. 2ff.]. The creation of new business models require smart products [4, p. 1, 5, p. 235, 6, p. 13, 7, p. 2, 8, p. 322, 9, p. 7]. The required data base for new business models cannot be provided by SMEs alone, whereas smart products are able to provide a foundation, given the creation of smart data and smart services they enable [5, p. 235]. These services then expand functions and functionality of smart products and define new business models [10, 6f.]. However, the development of smart products by small and medium-sized enterprises is still lined with obstacles [11, p. 640]. Regarding the product development process the inclusion of smart products means that new and SME-unknown domains diffuse during the process [12, p. 2]. Although there are many models regarding this process there appears to be a substantial lack of taking into account the competencies enabled by the implementation of digital technologies. Hence, several SME-supporting approaches fail to address the two major challenges these enterprises are faced with [13, p. 8]. This paper generally describes valid objectives containing relevant stakeholders and their allocation to the phases of the product life cycle. Within each objective the potential benefit for customers and producers is analyzed. The model given in this paper helps SMEs in defining the initiation of a product development project more precisely and hence also eases project scoping and targeting for the smartification of an already existing product

The Plasma and Suprathermal Ion Composition (PLASTIC) investigation on the STEREO observatories

The Plasma and Suprathermal Ion Composition (PLASTIC) investigation provides the in situ solar wind and low energy heliospheric ion measurements for the NASA Solar Terrestrial Relations Observatory Mission, which consists of two spacecraft (STEREO-A, STEREO-B). PLASTIC-A and PLASTIC-B are identical. Each PLASTIC is a time-of-flight/energy mass spectrometer designed to determine the elemental composition, ionic charge states, and bulk flow parameters of major solar wind ions in the mass range from hydrogen to iron. PLASTIC has nearly complete angular coverage in the ecliptic plane and an energy range from ∼0.3 to 80 keV/e, from which the distribution functions of suprathermal ions, including those ions created in pick-up and local shock acceleration processes, are also provided

First multispacecraft ion measurements in and near the Earth’s magnetosphere with the identical Cluster ion spectrometry (CIS) experiment

On board the four Cluster spacecraft, the Cluster Ion Spectrometry (CIS) experiment measures the full, three-dimensional ion distribution of the major magnetospheric ions (H+, He+, He++, and O+) from the thermal energies to about 40 keV/e. The experiment consists of two different instruments: a COmposition and DIstribution Function analyser (CIS1/CODIF), giving the mass per charge composition with medium (22.5°) angular resolution, and a Hot Ion Analyser (CIS2/HIA), which does not offer mass resolution but has a better angular resolution (5.6°) that is adequate for ion beam and solar wind measurements. Each analyser has two different sensitivities in order to increase the dynamic range. First tests of the instruments (commissioning activities) were achieved from early September 2000 to mid January 2001, and the operation phase began on 1 February 2001. In this paper, first results of the CIS instruments are presented showing the high level performances and capabilities of the instruments. Good examples of data were obtained in the central plasma sheet, magnetopause crossings, magnetosheath, solar wind and cusp measurements. Observations in the auroral regions could also be obtained with the Cluster spacecraft at radial distances of 4–6 Earth radii. These results show the tremendous interest of multispacecraft measurements with identical instruments and open a new area in magnetospheric and solar wind-magnetosphere interaction physics.Key words. Magnetospheric physics (magnetopause, cusp and boundary layers; magnetopheric configuration and dynamics; solar wind - magnetosphere interactions