Separating chemotherapy-related developmental neurotoxicity from cytotoxicity in monolayer and neurosphere cultures of human fetal brain cells

Chemotherapy-induced neurotoxicity can reduce the quality of life of patients by affecting their intelligence, senses and mobility. Ten percent of safety-related late-stage clinical failures are due to neurological side effects. Animal models are poor in predicting human neurotoxicity due to interspecies differences and most in vitro assays cannot distinguish neurotoxicity from general cytotoxicity for chemotherapeutics. We developed in vitro assays capable of quantifying the paediatric neurotoxic potential for cytotoxic drugs. Mixed cultures of human fetal brain cells were differentiated in monolayers and as 3D-neurospheres in the presence of non-neurotoxic chemotherapeutics (etoposide, teniposide) or neurotoxicants (methylmercury). The cytotoxic potency towards dividing progenitors versus differentiated neurons and astrocytes was compared using: (1) immunohistochemistry staining and cell counts in monolayers; (2) through quantitative Western blots in neurospheres; and (3) neurosphere migration assays. Etoposide and teniposide, were 5–10 times less toxic to differentiated neurons compared to the mix of all cells in monolayer cultures. In contrast, the neurotoxicant methylmercury did not exhibit selectivity and killed all cells with the same potency. In 3D neurospheres, etoposide and teniposide were 24 to 10 times less active against neurons compared to all cells. These assays can be used prioritise drugs for local drug delivery to brain tumours

In vitro models of medulloblastoma: choosing the right tool for the job

The recently-defined four molecular subgroups of medulloblastoma have required updating of our understanding of in vitro models to include molecular classification and risk stratification features from clinical practice. This review seeks to build a more comprehensive picture of the in vitro systems available for modelling medulloblastoma. The subtype classification and molecular characterisation for over 40 medulloblastoma cell-lines has been compiled, making it possible to identify the strengths and weaknesses in current model systems. Less than half (18/44) of established medulloblastoma cell-lines have been subgrouped. The majority of the subgrouped cell-lines (11/18) are Group 3 with MYC-amplification. SHH cell-lines are the next most common (4/18), half of which exhibit TP53 mutation. WNT and Group 4 subgroups, accounting for 50% of patients, remain underrepresented with 1 and 2 cell-lines respectively. In vitro modelling relies not only on incorporating appropriate tumour cells, but also on using systems with the relevant tissue architecture and phenotype as well as normal tissues. Novel ways of improving the clinical relevance of in vitro models are reviewed, focusing on 3D cell culture, extracellular matrix, co-cultures with normal cells and organotypic slices. This paper champions the establishment of a collaborative online-database and linked cell-bank to catalyse preclinical medulloblastoma research

Grain reconstruction and determination of grain attributes from MD data sets of FCC polycrystals

International audienceAn algorithm for the identification and reconstruction of crystallites from molecular dynamics data sets of FCC materials was developed. The algorithm was tested in an Al polycrystal possessing a weak texture. For the conditions tested, the algorithm was able to find all of the input orientations and reconstruct the grains according to their crystallographic orientation. The method is capable of calculating specific attributes of grains, namely, volume, center of mass, average orientation and orientation spread. The method additionally provides a mapping method to track grains during time-row dataset. The software uses shared-memory parallelization implemented by the use of the OpenMP-API, which enables a fast analysis of large volumes of data with excellent performance

Microwave Guiding of Electrons on a Chip

Electrons travelling in free space have allowed to explore fundamental physics like the wave nature of matter, the Aharonov-Bohm and the Hanbury Brown-Twiss effect. Complementarily, the precise control over the external degrees of freedom of electrons has proven pivotal for wholly new types of experiments such as high precision measurements of the electron's mass and magnetic moment in Penning traps. Interestingly, the confinement of electrons in the purely electric field of an alternating quadrupole has rarely been considered. Recent advances in the development of planar chip-based ion traps suggest that this technology can be applied to enable entirely new experiments with electron beams guided in versatile potentials. Here we demonstrate the transverse confinement of a low energy electron beam in a linear quadrupole guide based on microstructured planar electrodes and driven at microwave frequencies. A new guided matter-wave system will result, with applications ranging from electron interferometry to novel non-invasive electron microscopy

Failure analysis using scanning acoustic microscopy for diagnostics of electronic devices and 3D system integration technologies

New semiconductor chip technologies and technologies for 3D integration require information’s of packaging and interface defects in 3 dimensions, that means the lateral dimension of the defect and the location inside the device or package must be defined. In this paper, new methodical approaches for non destructive failure analysis on 3D integrated TSV samples are introduced. The concepts combine improved scanning acoustic microscopy (SAM) imaging hardware with unique software solutions for defect identification and quantitative analysis of mechanical properties using scanning acoustic investigations. In case of MEMS 3D integration, e.g. based on direct bonding, related interface defects must be investigated by SAM. With respect to 3D integration applications, the potential of recent SAM improvements applying specifically adapted hardware and custom-made signal processing algorithms will be discussed. Examples of SAM-based failure detection techniques for the application in 3D integration are demonstrated. New technologies are shown to improve the through put of fully wafer scanning using scanning acoustic microscopy. To improve the defect resolution, a new transducer design was developed to increase defect resolution and signal to noise for interface characterisation

Defect detection in through silicon vias by GHz scanning acoustic microscopy: Key ultrasonic characteristics

Among the technological developments pushed by the emergence of 3D-ICs, Through Silicon Via (TSV) technology has become a standard element in device processing over the past years. As volume increases, defect detection in the overall TSV formation sequence is becoming a major element of focus nowadays. Robust methods for in-line void detection during TSV processing are therefore needed especially for scaled down dimensions. Within this framework, the current contribution describes the application field of GHz Scanning Acoustic Microscopy (SAM) to TSV void detection