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The histopathology slide seminar “Classic Examples in Toxicologic Pathology XXVII” was held on February 21 and 22, 2020, at the Department of Pathology at the University of Veterinary Medicine in Hannover, Germany, with joint organization by the European Society of Toxicologic Pathology. The goal of this annual seminar is to present and discuss classical and actual cases of toxicologic pathology. This article summarizes the presentations given during the seminar, including images of representative lesions. Ten actual and classical cases of toxicologic pathology, mostly induced by a test article, were presented. These included small intestine pathology and transcriptomics induced by a γ-secretase modulator, liver findings in nonhuman primates induced by gene therapy, drug-induced neutropenia in dogs, device-induced growth plate lesions, polycystic lesions in CAR/PXR double knockout mice, inner ear lesions in transgenic mice, findings in Beagle dogs induced by an inhibitor of the myeloid leukemia cell differentiation protein MCL1, findings induced by a monovalent fibroblast growth factor receptor 1 antagonist, kidney lesions induced by a mammalian target of rapamycin inhibitor in combination therapy, and findings in mutation-specific drugs.

High power semiconductor disk lasers (SDLs) with near-diffraction limited beam quality were demonstrated. The influence of the incident angle, operation temperature, cavity length and curvature radius of the output coupler mirror on the beam quality were investigated. The condition for near-diffraction limited beam quality was analyzed. Choosing the pump spot size 10%–20% smaller than the fundamental mode size is the roughly optimized condition for achieving near-diffraction limited beam quality in SDLs. Finally, the SDL with an output power of 12.9 W and M2

Lateral $\beta $ -Ga2O3 MOSFET for power switching applications with a 1.8 kV breakdown voltage and a record power figure of merit of 155 MW/cm2 are demonstrated. Sub- $\mu \text{m}$ gate length combined with gate recess was used to achieve low ON-state resistances with reasonable threshold voltages above −24 V. The combination of compensation-doped high-quality crystals, implantation-based inter-device isolation, and SiN x -passivation yielded in consistently high average breakdown field strengths of 1.8–2.2 MV/cm for gate–drain spacings between 2 and 10 $\mu \text{m}$ . These values outperform the results of more established wide-bandgap device technologies, such as SiC or GaN, and the major Ga2O3 material promise—a higher breakdown strength—is well demonstrated.

High power semiconductor disk lasers (SDLs) were demonstrated based on the thermal management using pre-metalized diamond heat-spreader. The processing of pre-metallization using Cu-Sn alloy was developed. The resultant and influence of pre-metallization on the thermal performance of SDLs were investigated. It was found that the pre-metalized diamond heat-spreader was able to improve effectively not only the thermal resistance but also the bonding quality. 38% decrease on the thermal resistance of SDL was realized. The CW power exceeding 27 W, limited by the available pump power, was demonstrated.

Beta-gallium oxide (β-Ga2O3) is an emerging ultra-wide bandgap (4.8 eV) [1] semiconductor material. The high band gap leads to a theoretical breakdown field strength of 8 MV/cm [2], which enables the potential for β-Ga2O3 to outperform SiC and GaN and to become the next generation of high-performance material with respect to power electronic applications. Since transistors based on β-Ga2O3 benefit from a low on-resistance at a given breakdown voltage less power losses within a transistor switching operation can be achieved [3]. Thereby the electrically active part of the device is made up of a homoepitaxial thin layer. To fulfil the requirements from the device side, the epitaxial β-Ga2O3 layer has to have high crystalline perfections. To achieve such high quality layers was the aim of this work. β-Ga2O3 thin layer were grown homoepitaxially by MOVPE [4, 5] on Mg-doped β-Ga2O3 (100) substrates [6] with 2°, 4° and 6° miscut [7]. A development of the growth process with respect to growth modes and growth rate has been done. The Investigations were focusing on the interplay of the technical parameters i.e.: chamber pressure, Ar- push gas, precursor flux and their ratios. A transition from 2D island to step flow to step bunching growth modes has been achieved by varying the chamber pressure and/or the Ga/O2 ratio. This work shows that an adjusting of the effective diffusion length to the substrate step width is crucial to obtain step flow growth and with that high quality β-Ga2O3 (100) layers with electron mobilities above 150 cm²/Vs.

ABT-736 is a humanized monoclonal antibody generated to target a specific conformation of the amyloid-beta (Aβ) protein oligomer. Development of ABT-736 for Alzheimer’s disease was discontinued due to severe adverse effects (AEs) observed in cynomolgus monkey toxicity studies. The acute nature of AEs observed only at the highest doses suggested potential binding of ABT-736 to an abundant plasma protein. Follow-up investigations indicated polyspecificity of ABT-736, including unintended high-affinity binding to monkey and human plasma protein platelet factor 4 (PF-4), known to be involved in heparin-induced thrombocytopenia (HIT) in humans. The chronic AEs observed at the lower doses after repeat administration in monkeys were consistent with HIT pathology. Screening for a backup antibody revealed that ABT-736 possessed additional unintended binding characteristics to other, unknown factors. A subsequently implemented screening funnel focused on nonspecific binding led to the identification of h4D10, a high-affinity Aβ oligomer binding antibody that did not bind PF-4 or other unintended targets and had no AEs in vivo. This strengthened the hypothesis that ABT-736 toxicity was not Aβ target-related, but instead was the consequence of polyspecificity including PF-4 binding, which likely mediated the acute and chronic AEs and the HIT-like pathology. In conclusion, thorough screening of antibody candidates for nonspecific interactions with unrelated molecules at early stages of discovery can eliminate candidates with polyspecificity and reduce potential for toxicity caused by off-target binding.

Abstract Over the past 10 years, the interest in intranasal drug delivery in pharmaceutical R&D has increased. This review article summarises information on intranasal administration for local and systemic delivery, as well as for CNS indications. Nasal delivery offers many advantages over standard systemic delivery systems, such as its non-invasive character, a fast onset of action and in many cases reduced side effects due to a more targeted delivery. There are still formulation limitations and toxicological aspects to be optimised. Intranasal drug delivery in the field of drug development is an interesting delivery route for the treatment of neurological disorders. Systemic approaches often fail to efficiently supply the CNS with drugs. This review paper describes the anatomical, histological and physiological basis and summarises currently approved drugs for administration via intranasal delivery. Further, the review focuses on toxicological considerations of intranasally applied compounds and discusses formulation aspects that need to be considered for drug development. Graphical abstract

The European Society of Toxicologic Pathology organized an expert workshop in May 2018 to address adversity considerations related to thyroid follicular cell hypertrophy and/or hyperplasia (FCHH), which is a common finding in nonclinical toxicity studies that can have important implications for risk assessment of pharmaceuticals, food additives, and environmental chemicals. The broad goal of the workshop was to facilitate better alignment in toxicologic pathology and regulatory sciences on how to determine adversity of FCHH. Key objectives were to describe common mechanisms leading to thyroid FCHH and potential functional consequences; provide working criteria to assess adversity of FCHH in context of associated findings; and describe additional methods and experimental data that may influence adversity determinations. The workshop panel was comprised of representatives from the European Union, Japan, and the United States. Participants shared case examples illustrating issues related to adversity assessments of thyroid changes. Provided here are summary discussions, key case presentations, and panel recommendations. This information should increase consistency in the interpretation of adverse changes in the thyroid based on pathology findings in nonclinical toxicity studies, help integrate new types of biomarker data into the review process, and facilitate a more systematic approach to communicating adversity determinations in toxicology reports.

In this paper, we have demonstrated a 1.3 W green laser using a V-shaped intracavity frequency doubling 1036 nm semiconductor disk laser. The beam quality of the fundamental and second harmonic generation (SHG) laser is investigated. It has been found that the output lasers at the fundamental and SHG wavelength both suffer from reduced beam quality along with power scaling. The measured beam profile is elliptical under high power operation. In order to improve the SHG laser beam, an intracavity aperture is employed to control the mode characteristics of fundamental frequency light. By fine-tuning the aperture, a nearly circular beam profile with improving beam quality and brightness is realized.

In the course of development of transparent semiconducting oxides (TSOs) we compare the growth and basic physical properties bulk single crystals of ultra-wide bandgap (UWBG) TSOs, namely β-Ga2O3 and Ga-based spinels MgGa2O4, ZnGa2O4, and Zn1-xMgxGa2O4. High melting points of the materials of about 1800 -1930 °C and their thermal instability, including incongruent decomposition of Ga-based spinels, require additional tools to obtain large crystal volume of high structural quality that can be used for electronic and optoelectronic devices. Bulk β-Ga2O3 single crystals were grown by the Czochralski method with a diameter up to 2 inch, while the Ga-based spinel single crystals either by the Czochralski, Kyropoulos-like, or vertical gradient freeze / Bridgman methods with a volume of several to over a dozen cm3. The UWBG TSOs discussed here have optical bandgaps of about 4.6 - 5 eV and great transparency in the UV / visible spectrum. The materials can be obtained as electrical insulators, n-type semiconductors, or n-type degenerate semiconductors. The free electron concentration (ne) of bulk β-Ga2O3 crystals can be tuned within three orders of magnitude 1016 - 1019 cm−3 with a maximum Hall electron mobility (μ) of 160 cm2V−1s−1, that gradually decreases with ne. In the case of the bulk Ga-based spinel crystals with no intentional doping, the maximum of ne and μ increase with decreasing the Mg content in the compound and reach values of about 1020 cm−3 and about 100 cm2V−1s−1 (at ne > 1019 cm−3), respectively, for pure ZnGa2O4.

In this work, the fabrication of high-performance metal-oxide-semiconductor field-effect transistors (MOSFETs) on Si-doped homoepitaxial layers on (100) Mg-doped semi-insulating β-Ga2O3 substrates is demonstrated. Furthermore, the influence of additional gate and source field-plates is analyzed in regards to the breakdown properties of the MOSFET devices. The comparative study reveals comparable transistor performances of devices with and without field-plates showing maximum drain currents, on/off-current ratios and ON-resistances of ~75 mA/mm, 109 and 110 Ω∙mm, respectively. Moreover, both MOSFET structures show comparable breakdown voltages at around 1200 V which equals an average breakdown field strength of 2 MV/cm emphasizing no influence of the field-plates on the breakdown properties. Analysis of the thin film composition by secondary ion mass spectrometry on the processed β-Ga2O3 wafers indicates an increased concentration of silicon dopants at the interface between epitaxial layer and substrate. Our findings suggest that this might be the current main limitation factor in reaching higher breakdown voltages using field-plated β-Ga2O3 MOSFET devices.

We report the first demonstration of self-aligned gate (SAG) β-Ga2O3 metal-oxide-semiconductor field-effect transistors (MOSFETs) as a path toward eliminating source access resistance for low-loss power applications. The SAG process is implemented with a subtractively defined and etched refractory metal, such as Tungsten, combined with ion-implantation. We report experimental and modeled DC performance of a representative SAG device that achieved a maximum transconductance of 35 mS mm−1 and an on-resistance of ∼30 Ω mm with a 2.5 μm gate length. These results highlight the advantage of implant technology for SAG β-Ga2O3 MOSFETs enabling future power switching and RF devices with low parasitic resistance.

Current therapies for anemia associated with high hepcidin have limited success. Humanized monoclonal antibodies targeting hemojuvelin decrease hepcidin and improve anemia in three preclinical models. The antihemojuvelin antibodies were successfully applied to a mouse and a rat model of ACD (anemia

The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.

Cost efficient design of embedded HW/SW systems that need to meet certain requirements is a complex task due to the huge number of possible solutions, the ”design space”. Design space exploration methods depend on the designers' input in terms of application description, target architecture, and cost estimates for implementation alternatives. Obtaining feasible pre-implementation cost estimates causes lots of effort since the designer does not have confident information before implementation on the target architecture, or even different target architectures, has been performed. In this paper we present a methodology suitable for automatic cost estimation of synchronous data flow (SDF) graphs. We propose to start from an executable SystemC-AMS SDF specification, and demonstrate its automatic transformation and implementation for cost estimation on heterogeneous HW/SW architectures. The presented methodology allows the estimation of both HW and SW implementation alternatives of each SDF node based on a quick synthesis approach. These cost estimates are fed to a mapping framework to obtain a static binding and schedule for the architectures under exploration. With the proposed methodology the designer does not have to perform full synthesis and implementation for design space exploration. This is demonstrated by a case study of a Bluetooth baseband unit considered for implementation on a Xilinx Virtex-5 FPGA.

Reconfigurable architectures are often said to be able to exploit the possibilities of resource savings by means of hardware time-sharing. However, existing literature does not point clearly at which conditions must be fulfilled for considering a reconfigurable architecture for the implementation of signal processing applications. Therefore, we propose a fast method to perform high-level pre-implementation feasibility-based evaluation of a reconfigurable hardware implementation. The method is based on a light architectural model to compute costs of a static reference as well as costs for globally and partially reconfigurable architectures. Two case studies have been performed for an FFT and an FPGA-based DAB application. Our results show that implementation on reconfigurable architectures is only feasible when the reconfiguration time is low, which generally means that a dynamically partially reconfigurable solution is preferred.

This paper presents an investigation of the challengesin efficient programming of a DS-CDMA descrambling anddespreading application for the Cell Broadband Engine(CBE) architecture. A signal model of the DS-CDMA de-scrambling and despreading operations, exploitable by theCBE, is proposed. Based on the signal model partition-ing and extraction of parallelism is conducted and imple-mented. The tests show that the initial implementation isable to demodulate a 10 ms communication burst in 84.2ms with a utilization of 10.3% of the theoretical maximal76.8 GFLOPS. We identify that the rather low utilization isdue to the initial problem partitioning and propose a moreefficient partitionning solution.

Reconfigurable systems are expected to become more and more important as flexibility is becoming a requirement for many telecommunication applications. In this work, a methodology for handling dynamic partial reconfigurability is presented. The methodology builds on and extends the Rugby model and is applied to a case-study for implementation of two link-adaptation algorithms for WiMAX on a Xilinx Virtex-4 SX35 FPGA. The results indicate that implementation of dynamic partial reconfiguration can be handled well by the proposed methodology.

Multirate filters provide efficient filtering compared to traditional linear time-invariant filters. This paper introduces multirate filters and suggests the application of multirate filters for Single Side Band (SSB) demodulation. Implementing the filters in configurable logic provides the opportunity to reduce the bit-width and thereby area usage. The work is split into two; 1) The finite word length effects are analyzed by simulation in SystemC and a word length trade-off is selected. 2) The simulation results are verified by implementation on an Altera Stratix II FPGA EP2S60 kit, using DSP Builder.

The use of sensitive biomarkers to monitor skeletal muscle toxicity in preclinical toxicity studies is important for the risk assessment in humans during the development of a novel compound. Skeletal muscle toxicity in Sprague Dawley Rats was induced with clofibrate at different dose levels for 7 days to compare standard clinical pathology assays with novel skeletal muscle and cardiac muscle biomarkers, gene expression and histopathological changes. The standard clinical pathology assays aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) enzyme activity were compared to novel biomarkers fatty acid binding protein 3 (Fabp3), myosin light chain 3 (Myl3), muscular isoform of CK immunoreactivity (three isoforms CKBB, CKMM, CKMB), parvalbumin (Prv), skeletal troponin I (sTnI), cardiac troponin T (cTnT), cardiac troponin I (cTnI), CKMM, and myoglobin (Myo). The biomarker elevations were correlated to histopathological findings detected in several muscles and gene expression changes. Clofibrate predominantly induced skeletal muscle toxicity of type I fibers of low magnitude. Useful biomarkers for skeletal muscle toxicity were AST, Fabp3, Myl3, (CKMB) and sTnI. Measurements of CK enzyme activity by a standard clinical assay were not useful for monitoring clofibrate-induced skeletal muscle toxicity in the rat at the doses used in this study.

Spinal cord injury (SCI) is a devastating condition characterized by loss of function, secondary to damaged spinal neurons, disrupted axonal connections, and myelin loss. Spontaneous recovery is limited, and there are no approved pharmaceutical treatments to reduce ongoing damage or promote repair. Repulsive guidance molecule A (RGMa) is upregulated following injury to the central nervous system (CNS), where it is believed to induce neuronal apoptosis and inhibit axonal growth and remyelination. We evaluated elezanumab, a human anti-RGMa monoclonal antibody, in a novel, newly characterized non-human primate (NHP) hemicompression model of thoracic SCI. Systemic intravenous (IV) administration of elezanumab over 6 months was well tolerated and associated with significant improvements in locomotor function. Treatment of animals for 16 weeks with a continuous intrathecal infusion of elezanumab below the lesion was not efficacious. IV elezanumab improved microstructural integrity of extralesional tissue as reflected by higher fractional anisotropy and magnetization transfer ratios in treated vs. untreated animals. IV elezanumab also reduced SCI-induced increases in soluble RGMa in cerebrospinal fluid, and membrane bound RGMa rostral and caudal to the lesion. Anterograde tracing of the corticospinal tract (CST) from the contralesional motor cortex following 20 weeks of IV elezanumab revealed a significant increase in the density of CST fibers emerging from the ipsilesional CST into the medial/ventral gray matter. There was a significant sprouting of serotonergic (5-HT) fibers rostral to the injury and in the ventral horn of lower thoracic regions. These data demonstrate that 6 months of intermittent IV administration of elezanumab, beginning within 24 h after a thoracic SCI, promotes neuroprotection and neuroplasticity of key descending pathways involved in locomotion. These findings emphasize the mechanisms leading to improved recovery of neuromotor functions with elezanumab in acute SCI in NHPs.