Impact of Glutathione Modulation on Stability and Pharmacokinetic Profile of Redox‐Sensitive Nanogels

Nanoparticles degradable upon external stimuli combine pharmacokinetic features of both small molecules as well as large nanoparticles. However, despite promising preclinical results, several redox responsive disulphide‐linked nanoparticles failed in clinical translation, mainly due to their unexpected in vivo behavior. Glutathione (GSH) is one of the most evaluated antioxidants responsible for disulfide degradation. Herein, the impact of GSH on the in vivo behavior of redox‐sensitive nanogels under physiological and modulated conditions is investigated. Labelling of nanogels with a DNA‐intercalating dye and a radioisotope allows visualization of the redox responsiveness at the cellular and the systemic levels, respectively. In vitro, efficient cleavage of disulphide bonds of nanogels is achieved by manipulation of intracellular GSH concentration. While in vivo, the redox‐sensitive nanogels undergo, to a certain extent, premature degradation in circulation leading to rapid renal elimination. This instability is modulated by transient inhibition of GSH synthesis with buthioninsulfoximin. Altered GSH concentration significantly changes the in vivo pharmacokinetics. Lower GSH results in higher elimination half‐life and altered biodistribution of the nanogels with a different metabolite profile. These data provide strong evidence that decreased nanogel degradation in blood circulation can limit the risk of premature drug release and enhance circulation half‐life of the nanogel.     

An algorithmically consistent macroscopic tangent operator for FFT‐based computational homogenization

The present work addresses a multiscale framework for fast‐Fourier‐transform–based computational homogenization. The framework considers the scale bridging between microscopic and macroscopic scales. While the macroscopic problem is discretized with finite elements, the microscopic problems are solved by means of fast‐Fourier‐transforms (FFTs) on periodic representative volume elements (RVEs). In such multiscale scenario, the computation of the effective properties of the microstructure is crucial. While effective quantities in terms of stresses and deformations can be computed from surface integrals along the boundary of the RVE, the computation of the associated moduli is not straightforward. The key contribution of the present paper is the derivation and implementation of an algorithmically consistent macroscopic tangent operator which directly resembles the effective moduli of the microstructure. The macroscopic tangent is derived by means of the classical Lippmann‐Schwinger equation and can be computed from a simple system of linear equations. This is performed through an efficient FFT‐based approach along with a conjugate gradient solver. The viability and efficiency of the method is demonstrated for a number of two‐ and three‐dimensional boundary value problems incorporating linear and nonlinear elasticity as well as viscoelastic material response.     

Identification of Martensite Bands in Dual-Phase Steels: A Deep Learning Object Detection Approach Using Faster Region-Based-Convolutional Neural Network

Martensite banding in dual-phase steels is an important research topic in the field of materials design, since it affects the local damage properties of the material largely. Therefore, it is necessary to quantify the amount and the geometrical details of the bands in a specific microstructure, for example, for simulative approaches. A convolutional neural network is trained on manually labeled scanning electron microscopy images of DP800 steel and a subsequent effort is made to transfer these results to statistical quantities for the generation of representative volume elements (RVE). As exact geometric definitions of martensite bands in 2D are difficult, the influence of different band definitions is investigated. The result of the training shows good prediction accuracy but is strongly dependent on the chosen band definition and the underlying human bias from the labeling process. A statistical analysis using cross-validation shows that reliable results can already be achieved with only small datasets of around 50–100 training images due to the transfer learning approach. This is an important outcome as it eliminates the need to generate a large dataset which can only be obtained from time-consuming microscopy work and manual labeling of the images.     

Resistance against Abrasive Wear and Corrosion of Laser Powder Bed Alloyed High Chromium Tool Steels

Additive manufacturing by laser-based powder bed fusion of metals (PBF-LB/M) enables the production of complex shaped components. High-carbon tool steels tend to cracking during PBF-LB/M due to internal stresses caused by the rapid solidification. Expensive atomization and long lead times for powder generate high costs in this processing route. In situ alloying during PBF-LB/M of powder blends from conventionally available powders enables a more flexible approach of alloy design. For industrial use, the mechanical properties of in situ alloyed parts must be comparable to those of conventionally manufactured parts. In some cutting and forming applications, high wear resistance and corrosion resistance are required simultaneously. High alloyed cold work tool steels with sufficient chromium solved in the metal matrix fulfill these demands. Herein, AISI H13 is modified by Cr₃C₂ and elemental Cr to suit these requirements. Two novel alloys are modeled thermodynamically and processed by PBF-LB/M. In-depth microstructural investigations by backscatter electron imaging and diffraction in combination with abrasive wear tests and potentiodynamic polarization curves allow microstructure property correlations for different heat-treated conditions. Partial crack-free processing, hardenability, formation of Cr-rich carbides, and residual Cr-rich inclusions are observed and their influence on the wear and corrosion resistance is discussed.     

Teaching adults new words: The role of practice and consolidation.

Semantic and orthographic learning of new words was investigated with the help of the picture-word interference (PWI) task. In this version of the Stroop task, picture naming is delayed by the simultaneous presentation of a semantically related as opposed to an unrelated distractor word (a specific PWI effect), as well as by an unrelated word compared with a nonword (a general PWI effect). This interference is taken to reflect automatic orthographic and semantic processing. The authors observed that participants showed both types of PWI effects for newly learned words following a single study session. Interestingly, specific PWI effects were not obtained immediately after testing but did emerge a week later without additional practice. This suggests that a period of consolidation is involved in the establishment of word representations. In addition, identical PWI effects were obtained when the study and test words were presented in either the same or different letter case. This provides evidence that the newly acquired orthographic representations are coded in an abstract format. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Wood viscoelastic compliance determination with special attention to measurement problems

A new experimental technique has been developed for the determination of wood viscoelastic compliance in tension. It associates tensile creep tests parallel to, and off the material symmetry axes with a strain measurement system using a rosette gauge. Particular attention has been paid to accurate strain measurement, and to hydrothermal and mechanical disturbance factors. Application is restricted to the determination of the four compliances which characterize the viscoelastic behaviour of spruce in the LR (radial) plane, at 21°C and 12% equilibrium moisture content. The time-dependent strain induced by load level up to 58% of the ultimate strength, and applied during 4 to 10 days, is largely recoverable. As proposed by Schniewind and Barrett, the compliances are represented by time power functions. The experimental results support earlier observations that the creep level is much higher in tension in the radial direction than parallel to the grain, and that the creep level in shear over the LR plane is an intermediate between the above two cases. Finally, the experimental results illustrate the validity of the superposition principle under the test conditions examined, which is the basis of the linear viscoelastic model introduced here.

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Resume On présente une méthode d’essais originale pour la détermination des complaisances viscoélastiques du bois sans défaut en traction. Elle combine des essais de fluage en traction d’éprouvettes taillées suivant les axes d’anisotropie et taillées avec un angle de désorientation (essais ‘hors axes’). Le mesurage des déformations est effectué par des jauges d’extensométrie (rosettes). Préalablement aux essais, il a été réalisé une réflexion méthodologique portant sur les essais de traction sur bois sans défaut et une analyse expérimentale de la stabilité au cours du temps des systèmes de mesurage (jauge/colle). Ce dernier point, lié aux effets mécaonosorptifs, nous a permis de préconiser l’utilisation des jauges KFC en association avec celle de la colle époxy.

     

MR of the eye with retrobulbar anesthesia

MR imaging with retrobulbar anesthesia was performed in eight patients with uveal melanoma. Injection of 2 mL prilocain hydrochloride in 2% epinephrin into the eye muscle cone resulted in improved image quality in seven patients, without side effects. Ocular MR imaging can be indicated to clarify indeterminate sonographic findings in cases of extrascleral growth or to exclude optic nerve invasion in patients with tumors located at the posterior pole of the globe.     

In vitro mutagenicity of the plasmacytomagenic agent pristane (2,6,10,14-tetramethylpentadecane)

Cystatin A is a cysteine proteinase inhibitor with a molecular mass of 11 kDa, and is located mainly in the keratohyaline granules of the stratum granulosum and the cornified envelope of the stratum corneum in the epidermis. In this study, we demonstrated the genomic structure of this proteinase inhibitor in which there were three exons of 111 bp, 102 bp and 226 bp in length, while the lengths of the 1st and 2nd intron were approximately 14 Kbp and 4 Kbp, respectively. The conserved sequence of QVVAG was encoded in the 2nd exon and was not inserted by any introns. There were binding sites for SP-1 and AP-2 in the promoter region and an AP-1 binding site in the 1st intron. The successful amplification of each exon of cystatin A may possibly contribute to the detection of the genomic abnormality of some skin disorders e.g. keratinization disorder, chronic bacterial infection or photophobia.     

Magnetic resonance imaging--guided abdominal interventional radiology: laser-induced thermotherapy of liver metastases

The aim of this study was to evaluate the clinical benefit of magnetic resonance imaging--guided laser-induced thermotherapy (LITT) for the minimally invasive treatment of liver metastases, with regard to survival rates and local tumor control. Magnetic resonance--guided LITT under local anesthesia was carried out in 134 consecutive patients aged 28-84 (mean age 69), with a total of 383 liver metastases. The major groups were liver metastases from colorectal cancer (88 patients) and liver metastases from breast cancer (20 patients), as well as metastases of miscellaneous primary tumors (26 patients). A total of 1048 laser applications were carried out. Cumulative survival times were calculated using the Kaplan-Meier method. All of the patients tolerated the procedure under local anesthesia well, and no severe complications or side effects were observed. During the follow-up period, 29 of the 134 patients treated died. The mean survival time was 35 months in the colorectal cancer group, 30 months in the breast cancer group, and 34 months in the group with miscellaneous primary tumors. The statistical assessment of the equality of survival distribution showed no significant differences between the three groups (Breslow test P = 0.35, Tarone-Ware test P = 0.49). These results suggest that in patients with liver metastases, local tumor destruction using minimally invasive percutaneous LITT under local anesthesia results in improved clinical outcomes, independently of the type of primary tumor.     

Phase II study on preoperative radio-chemo-thermotherapy in locally advanced rectal carcinoma

BACKGROUND: Recent studies show that preoperative radio-chemotherapy can increase resectability and local control of locally advanced rectal carcinomas. Additional regional hyperthermia might increase remission rates and tumor response. We therefore tested regional hyperthermia together with radio-chemotherapy in a phase-II study on locally advanced rectal carcinomas. PATIENTS AND METHODS: Thirty-seven patients with primary advanced stage uT3/T4 rectal carcinomas were treated with preoperative radio-chemo-thermo-therapy. The initial tumor depth was determined using endosonography, CT, and MRI. Radiotherapy was carried out in prone position (on a belly board) using standard techniques, with 5 x 1.8 Gy per week up to 45 Gy at the reference point. 5-Fluorouracil (300 to 500 mg/m2) was administered with low doses of leucovorin (50 mg) on days 1 to 5 and 22 to 28. The patients were treated with regional hyperthermia each week prior to radiotherapy and simultaneously with chemotherapy, using the Sigma 60 ring from the BSD-2000 system. Temperature/position curves and temperature/time curves were recorded in endocavitary (endorectal) catheters in tumor contact and as well in bladder and vagina. Following endosonographic restaging, the operation was carried out 4 to 6 weeks after the end of preoperative therapy and adjuvant chemotherapy continued in four cycles. In cases where tumors were non-resectable, a boost up to 64 Gy was aimed. RESULTS: Thirty-one of the 37 patients (84%) with primary carcinoma proved locally R0-resectable. In addition we had 1 R1-resection (3%) and 5 non-resectable tumors (13%). Among the resected tumors, 53% experienced a reduction of depth infiltration from the initial endosonographic stage during preoperative therapy. The actuarial survival rate after 4 years is 65% (free of progression 57%). The actuarial 4-year survival rate was particularly favorable for the group of responders. Overall, the preoperative multimodal therapy was well tolerated, and premature termination was only necessary in 1 case (3%). Grade III/IV toxicities in the intestine and skin were reduced as far as possible by field blockings and cooling of the perineal region. They occurred only in 5/37 patients (13%) at the intestine and in 6/37 patients (16%) at the skin. The thermal data were subjected to a statistical analysis. The quality of temperature distribution (T90, cum min T90 > or = 40.5 degrees C) depends on the power level and relative power density. The response (reduction of tumor size or depth infiltration) correlated significantly with quality parameters of the temperature distributions. This dependency is found as a trend for progression-free survival, too. CONCLUSIONS: Preoperative radio-chemo-thermo-therapy proved to be practical and effective, with encouraging remission rates and excellent local control rates. For this reason, a phase-III study to test regional hyperthermia has been initiated. At the same time, certain technical improvements are still under development for regional hyperthermia.