Search results for "preclinical"

Harmonization of QSAR Best Practices and Molecular Docking Provides an Efficient Virtual Screening Tool for Discovering New G-Quadruplex Ligands

2015

Telomeres and telomerase are key players in tumorogenesis. Among the various strategies proposed for telomerase inhibition or telomere uncapping, the stabilization of telomeric G-quadruplex (G4) structures is a very promising one. Additionally, G4 stabilizing ligands also act over tumors mediated by the alternative elongation of telomeres. Accordingly, the discovery of novel compounds able to act on telomeres and/or inhibit the telomerase enzyme by stabilizing DNA telomeric G4 structures as well as the development of approaches efficiently prioritizing such compounds constitute active areas of research in computational medicinal chemistry and anticancer drug discovery. In this direction, we…

2013

Background To monitor viability of implanted genetically engineered and microencapsulated human stem cells (MicroBeads) in the mouse eye, and to study the impact of the beads and/or xenogenic cells on retinal integrity. Methodology/Principal Findings MicroBeads were implanted into the subretinal space of SV126 wild type mice using an ab externo approach. Viability of microencapsulated cells was monitored by noninvasive retinal imaging (Spectralis™ HRA+OCT). Retinal integrity was also assessed with retinal imaging and upon the end of the study by light and electron microscopy. The implanted GFP-marked cells encapsulated in subretinal MicroBeads remained viable over a period of up to 4 months…

Sorafenib perpetuates cellular anti-cancer effector functions by modulating the cross talk between macrophages and natural killer cells.

2012

Alternatively polarized macrophages (Mϕ) shape the microenvironment of hepatocellular carcinoma (HCC) and temper anticancer immune responses. We investigated if sorafenib alters the HCC microenvironment by restoring classical macrophage polarization and triggering tumor-directed natural killer (NK) cell responses. In vivo experiments were conducted with sorafenib (25 mg/kg)-treated C57BL/6 wildtype as well as hepatitis B virus (HBV) and lymphotoxin transgenic mice with and without HCC. Monocyte-derived Mϕ or tumor-associated macrophages (TAM) isolated from HCC tissue were treated with sorafenib (0.07-5.0 μg/mL) and cocultured with autologous NK cells. Mϕ and NK cell activation was analyzed …

Simultaneous screening and quantification of aminoglycoside antibiotics in honey using mixed-mode liquid chromatography with quadrupole time-of-fligh…

2018

An analytical method based on liquid chromatography with quadrupole time-of-flight mass spectrometry has been developed for the simultaneous determination of six aminoglycoside antibiotics in honey. The sample pretreatment included extraction with aqueous trichloroacetic acid followed by solid-phase extraction on Strata-X polymeric reversed phase cartridges. Liquid chromatography separation was performed on an Obelisc R zwitterionic type mixed-mode column. An ionBooster™ heated electrospray source was used and showed enhanced ionization efficiency in comparison to a conventional electrospray source. The observed signal enhancement ranged from 3- (neomycin) to 16-fold (gentamicin C1). A data…

Funktionelle Bildgebung der Lunge mit gasförmigem Kontrastmittel: ³Helium-Magnetresonanztomographie

2005

Current imaging methods of the lung concentrate on morphology as well as on the depiction of the pulmonary parenchyma. The need of an advanced and more subtle imaging technology compared to conventional radiography is met by computed topography as the method of choice. Nevertheless, computed tomography yields very limited functional information. This is to be derived from arterial blood gas analysis, spirometry and body plethysmography. These methods, however, lack the scope for regional allocation of any pathology. Magnetic resonance imaging of the lung has been advanced by the use of hyperpolarised (3)Helium as an inhaled gaseous contrast agent. The inhalation of the gas provides function…

A new mathematical approach for the estimation of the AUC and its variability under different experimental designs in preclinical studies

2011

The aim of the present work was to develop a new mathematical method for estimating the area under the curve (AUC) and its variability that could be applied in different preclinical experimental designs and amenable to be implemented in standard calculation worksheets. In order to assess the usefulness of the new approach, different experimental scenarios were studied and the results were compared with those obtained with commonly used software: WinNonlin® and Phoenix WinNonlin®. The results do not show statistical differences among the AUC values obtained by both procedures, but the new method appears to be a better estimator of the AUC standard error, measured as the coverage of 95% confi…

Multicellular tumor spheroids: an underestimated tool is catching up again.

2009

The present article highlights the rationale, potential and flexibility of tumor spheroid mono- and cocultures for implementation into state of the art anti-cancer therapy test platforms. Unlike classical monolayer-based models, spheroids strikingly mirror the 3D cellular context and therapeutically relevant pathophysiological gradients of in vivo tumors. Some concepts for standardization and automation of spheroid culturing, monitoring and analysis are discussed, and the challenges to define the most convenient analytical endpoints for therapy testing are outlined. The potential of spheroids to contribute to either the elimination of poor drug candidates at the pre-animal and pre-clinical …

Digital Image Analysis Applied to Tumor Cell Proliferation, Aggressiveness, and Migration-Related Protein Synthesis in Neuroblastoma 3D Models

2020

Patient-derived cancer 3D models are a promising tool that will revolutionize personalized cancer therapy but that require previous knowledge of optimal cell growth conditions and the most advantageous parameters to evaluate biomimetic relevance and monitor therapy efficacy. This study aims to establish general guidelines on 3D model characterization phenomena, focusing on neuroblastoma. We generated gelatin-based scaffolds with different stiffness and performed SK-N-BE(2) and SH-SY5Y aggressive neuroblastoma cell cultures, also performing co-cultures with mouse stromal Schwann cell line (SW10). Model characterization by digital image analysis at different time points revealed that cell pro…

Structure-based engineering of strictosidine synthase: auxiliary for alkaloid libraries.

2007

SummaryThe highly substrate-specific strictosidine synthase (EC 4.3.3.2) catalyzes the biological Pictet-Spengler condensation between tryptamine and secologanin, leading to the synthesis of about 2000 monoterpenoid indole alkaloids in higher plants. The crystal structure of Rauvolfia serpentina strictosidine synthase (STR1) in complex with strictosidine has been elucidated here, allowing the rational site-directed mutation of the active center of STR1 and resulting in modulation of its substrate acceptance. Here, we report on the rational redesign of STR1 by generation of a Val208Ala mutant, further describing the influence on substrate acceptance and the enzyme-catalyzed synthesis of 10-m…

Reconstruction of hyperspectral cutaneous data from an artificial neural network-based multispectral imaging system.

2011

International audience; The development of an integrated MultiSpectral Imaging (MSI) system yielding hyperspectral cubes by means of artificial neural networks is described. The MSI system is based on a CCD camera, a rotating wheel bearing a set of seven interference filters, a light source and a computer. The resulting device has been elaborated for in vivo imaging of skin lesions. It provides multispectral images and is coupled with a software reconstructing hyperspectral cubes from multispectral images. Reconstruction is performed by a neural network-based algorithm using heteroassociative memories. The resulting hyperspectral cube provides skin optical reflectance spectral data combined…