Die filling process simulation using discrete element method (DEM)

Powder compaction and sintering are important techniques for the mass production of geometrically complex parts. Powder is poured from a reservoir into the feeding shoe, which then passes the cavity one or more times thereby delivering powder into it. The powder is then compressed to create a relatively brittle green body. Finally, the green body is ejected from the cavity and sintered in a furnace where thermal activation below the melting point produces a fully dense structure. Necks form and grow between adjacent grains thereby eliminating the porosity of the part. In general, a consistent and uniform die filling process is always desirable. Heterogeneity during die filling can propagate through the subsequent processes and finally lead to serious product defects, such as cracking, low strength, distortion and shrinkage [1]. Capillary cohesion is known to influence strongly the strength and flow properties of granular materials. At low levels of water content, the water forms a discontinuous phase composed of interparticle bridges that are unevenly distributed in the bulk (the pendular state) [2]. For powder filling process these capillary forces may have strong influence in the particle dynamics and subsequent packing. An approach using discrete element method (DEM) simulation is proposed to reproduce die filling process and investigate process characteristics that affect final sand cake shape and may lead to in-homogeneities in powder during the filling process. Also an experimental apparatus able to reproduce the die filling process was built to validate numerical model. A coarse grain model is also necessary to reduce the model size (reduce the number of particles)

Spatio-temporal gait analysis based on human-smart rollator interaction

The ability to walk is typically related to several biomechanical components that are involved in the gait cycle (or stride), including free mobility of joints, particularly in the legs; coordination of muscle activity in terms of timing and intensity; and normal sensory input, such as vision and vestibular system. As people age, they tend to slow their gait speed, and their balance is also affected. Also, the retirement from the working life and the consequent reduction of physical and social activity contribute to the increased incidence of falls in older adults. Moreover, older adults suffer different kinds of cognitive decline, such as dementia or attention problems, which also accentuate gait disorders and its consequences. In this paper we present a methodology for gait identification using the on-board sensors of a smart rollator: the i-Walker. This technique provides the number of steps performed in walking exercises, as well as the time and distance travelled for each stride. It also allows to extract spatio-temporal metrics used in medical gait analysis from the interpretation of the interaction between the individual and the i-Walker. In addition, two metrics to assess users’ driving skills, laterality and directivity, are proposed.Peer ReviewedPostprint (author's final draft

Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.

Melanoma is a devastating skin cancer characterized by distinct biological subtypes. Besides frequent mutations in growth- and survival-promoting genes like BRAF and NRAS, melanomas additionally harbor complex non-random genomic alterations. Using an integrative approach, we have analysed genomic and gene expression changes in human melanoma cell lines (N=32) derived from primary tumors and various metastatic sites and investigated the relation to local growth aggressiveness as xenografts in immuno-compromised mice (N=22). Although the vast majority >90% of melanoma models harbored mutations in either BRAF or NRAS, significant differences in subcutaneous growth aggressiveness became obvious. Unsupervised clustering revealed that genomic alterations rather than gene expression data reflected this aggressive phenotype, while no association with histology, stage or metastatic site of the original melanoma was found. Genomic clustering allowed separation of melanoma models into two subgroups with differing local growth aggressiveness in vivo. Regarding genes expressed at significantly altered levels between these subgroups, a surprising correlation with the respective gene doses (>85% accordance) was found. Genes deregulated at the DNA and mRNA level included well-known cancer genes partly already linked to melanoma (RAS genes, PTEN, AURKA, MAPK inhibitors Sprouty/Spred), but also novel candidates like SIPA1 (a Rap1GAP). Pathway mining further supported deregulation of Rap1 signaling in the aggressive subgroup e.g. by additional repression of two Rap1GEFs. Accordingly, siRNA-mediated down-regulation of SIPA1 exerted significant effects on clonogenicity, adherence and migration in aggressive melanoma models. Together our data suggest that an aneuploidy-driven gene expression deregulation drives local aggressiveness in human melanoma

FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal

Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells, respectively. The biphasic subtype contains a mixture of both. The sarcomatoid subtype expresses markers of epithelial-mesenchymal transition (EMT) and confers the worst prognosis, but the signals and pathways controlling EMT in MPM are not well understood. We demonstrate that treatment with FGF2 or EGF induced a fibroblastoid morphology in several cell lines from biphasic MPM, accompanied by scattering, decreased cell adhesion and increased invasiveness. This depended on the MAP-kinase pathway but was independent of TGF beta or PI3-kinase signaling. In addition to changes in known EMT markers, microarray analysis demonstrated differential expression of MMP1, ESM1, ETV4, PDL1 and BDKR2B in response to both growth factors and in epithelioid versus sarcomatoid MPM. Inhibition of MMP1 prevented FGF2-induced scattering and invasiveness. Moreover, in MPM cells with sarcomatoid morphology, inhibition of FGF/MAP-kinase signaling induced a more epithelioid morphology and gene expression pattern. Our findings suggest a critical role of the MAP-kinase axis in the morphological and behavioral plasticity of mesothelioma

A novel EGFR inhibitor acts as potent tool for hypoxia-activated prodrug systems and exerts strong synergistic activity with VEGFR inhibition in vitro and in vivo

Small-molecule EGFR inhibitors have distinctly improved the overall survival especially in EGFR-mutated lung cancer. However, their use is often limited by severe adverse effects and rapid resistance development. To overcome these limitations, a hypoxia-activatable Co(III)-based prodrug (KP2334) was recently synthesized releasing the new EGFR inhibitor KP2187 in a highly tumor-specific manner only in hypoxic areas of the tumor. However, the chemical modifications in KP2187 necessary for cobalt chelation could potentially interfere with its EGFR-binding ability. Consequently, in this study, the biological activity and EGFR inhibition potential of KP2187 was compared to clinically approved EGFR inhibitors. In general, the activity as well as EGFR binding (shown in docking studies) was very similar to erlotinib and gefitinib (while other EGFR-inhibitory drugs behaved different) indicating no interference of the chelating moiety with the EGFR binding. Moreover, KP2187 significantly inhibited cancer cell proliferation as well as EGFR pathway activation in vitro and in vivo. Finally, KP2187 proved to be highly synergistic with VEGFR inhibitors such as sunitinib. This indicates that KP2187releasing hypoxia-activated prodrug systems are promising candidates to overcome the clinically observed enhanced toxicity of EGFR-VEGFR inhibitor combination therapies

Landomycins as glutathione-depleting agents and natural fluorescent probes for cellular Michael adduct-dependent quinone metabolism

Landomycins are angucyclines with promising antineoplastic activity produced by Streptomyces bacteria. The aglycone landomycinone is the distinctive core, while the oligosaccharide chain differs within derivatives. Herein, we report that landomycins spontaneously form Michael adducts with biothiols, including reduced cysteine and glutathione, both cell-free or intracellularly involving the benz[a]anthraquinone moiety of landomycinone. While landomycins generally do not display emissive properties, the respective Michael adducts exerted intense blue fluorescence in a glycosidic chain-dependent manner. This allowed label-free tracking of the short-lived nature of the mono-SH-adduct followed by oxygen-dependent evolution with addition of another SH-group. Accordingly, hypoxia distinctly stabilized the fluorescent mono-adduct. While extracellular adduct formation completely blocked the cytotoxic activity of landomycins, intracellularly it led to massively decreased reduced glutathione levels. Accordingly, landomycin E strongly synergized with glutathione-depleting agents like menadione but exerted reduced activity under hypoxia. Summarizing, landomycins represent natural glutathione-depleting agents and fluorescence probes for intracellular anthraquinone-based angucycline metabolism

The land use change impact of biofuels consumed in the EU: Quantification of area and greenhouse gas impacts

Biofuels are promoted as an option to reduce climate emissions from the transport sector. As most biofuels are currently produced from land based crops, there is a concern that the increased consumption of biofuels requires agricultural expansion at a global scale, leading to additional carbon emissions. This effect is called Indirect Land Use Change, or ILUC. The EU Renewable Energy Directive (2009/28/EC) directed the European Commission to develop a methodology to account for the ILUC effect. The current study serves to provide new insights to the European Commission and other stakeholders about these indirect carbon and land impacts from biofuels consumed in the EU, with more details on production processes and representation of individual feedstocks than was done before. ILUC cannot be observed or measured in reality, because it is entangled with a large number of other changes in agricultural markets at both global and local levels. The effect can only be estimated through the use of models. The current study is part of a continuous effort to improve the understanding and representation of ILUC

Third CECOG consensus on the systemic treatment of non-small-cell lung cancer

The current third consensus on the systemic treatment of non-small-cell lung cancer (NSCLC) builds upon and updates similar publications on the subject by the Central European Cooperative Oncology Group (CECOG), which has published such consensus statements in the years 2002 and 2005 (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer—update 2004. Lung Cancer 2005; 50: 129-137). The principle of all CECOG consensus is such that evidence-based recommendations for state-of-the-art treatment are given upon which all participants and authors of the manuscript have to agree (Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). This is of particular importance in diseases in which treatment options depend on very particular clinical and biologic variables (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer—update 2004. Lung Cancer 2005; 50: 129-137; Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). Since the publication of the last CECOG consensus on the medical treatment of NSCLC, a series of diagnostic tools for the characterization of biomarkers for personalized therapy for NSCLC as well as therapeutic options including adjuvant treatment, targeted therapy, and maintenance treatment have emerged and strongly influenced the field. Thus, the present third consensus was generated that not only readdresses previous disease-related issues but also expands toward recent developments in the management of NSCLC. It is the aim of the present consensus to summarize minimal quality-oriented requirements for individual patients with NSCLC in its various stages based upon levels of evidence in the light of a rapidly expanding array of individual therapeutic option