Cancer cell invasion takes place at the cancer-host interface and is a prerequisite for distant metastasis. The relationships between current biological and clinical concepts such as cell migration modes, tumour budding and epithelial-mesenchymal transition (EMT) remains unclear in several aspects, especially for the 'real' situation in human cancer. We developed a novel method that provides exact three-dimensional (3D) information on both microscopic morphology and gene expression, over a virtually unlimited spatial range, by reconstruction from serial immunostained tissue slices. Quantitative 3D assessment of tumour budding at the cancer-host interface in human pancreatic, colorectal, lung and breast adenocarcinoma suggests collective cell migration as the mechanism of cancer cell invasion, while single cancer cell migration seems to be virtually absent. Budding tumour cells display a shift towards spindle-like as well as a rounded morphology. This is associated with decreased E-cadherin staining intensity and a shift from membranous to cytoplasmic staining, as well as increased nuclear ZEB1 expression.

Automatic Non-rigid Histological Image Registration (ANHIR) challenge was organized to compare the performance of image registration algorithms on several kinds of microscopy histology images in a fair and independent manner. We have assembled 8 datasets, containing 355 images with 18 different stains, resulting in 481 image pairs to be registered. Registration accuracy was evaluated using manually placed landmarks. In total, 256 teams registered for the challenge, 10 submitted the results, and 6 participated in the workshop. Here, we present the results of 7 wellperforming methods from the challenge together with 6 well-known existing methods. The best methods used coarse but robust initial alignment, followed by non-rigid registration, used multiresolution, and were carefully tuned for the data at hand. They outperformed off-the-shelf methods, mostly by being more robust. The best methods could successfully register over 98% of all landmarks and their mean landmark registration accuracy (TRE) was 0.44% of the image diagonal. The challenge remains open to submissions and all images are available for download.

A defect in the pksP gene of Aspergillus fumigatus is associated with the loss of conidial pigmentation, a profound change of the conidial surface structure, and reduced virulence. The structural change of the conidial surface structure was not observed in similar A. nidulans wA mutants. Our data indicate that the pigment of both species is important for scavenging reactive oxygen species and for protection of conidia against oxidative damage.Aspergillus spp. are the predominant causative agents of invasive pulmonary aspergillosis (IPA), an often lethal infection of the immunocompromised host (4,10,13,16). Since conidia are the infectious agent in IPA, recent studies focused on the elucidation of conidial factors contributing to pathogenicity (8,17). Previously, we and others have shown that conidia lacking pigmentation due to the defective polyketide synthase gene pksP were less resistant to the attack by monocytes in vitro and showed reduced virulence in a murine animal model (8,9,17,18). During these studies, it became apparent that coincubation of human phagocytes with pksP mutant conidia resulted in a marked increase in the release of reactive oxygen species (ROS) compared with wild-type (wt) conidia (8). Since a defective pksP gene not only impaired conidial pigmentation but concomitantly resulted in profound alterations of the conidial surface (8, 9), the question arose as to whether the large amounts of ROS detected after incubation of phagocytes with pksP mutant conidia were due to a change in the activation pattern of the cells or, alternatively, reflected the lack of ROS quenching capacity caused by the loss of conidial pigment. To address this question, conidia of wt strains of both Aspergillus fumigatus and the nonpathogenic fungus Aspergillus nidulans were compared with their respective pigmentless mutant strains.The WA mutant of A. nidulans (strain WG370; wA3 bgaO biA1) lacking the conidial pigment due to a defective polyketide synthase gene (wA) was constructed by a sexual cross of appropriate parental strains (12) using standard genetic techniques (14). The wA gene product might have a function similar to that of the pksP gene product of A. fumigatus, although major differences between the pigment biosyntheses of the two Aspergillus species exist (2, 18; this study).As previously reported, conidia of the A. fumigatus wt strain showed a rough surface; i.e., they had an ornamentation which was lacking in the pksP mutant strain (8, 9) ( Fig. 1A and B). The A. nidulans wt conidia showed a similar ornamentation (Fig. 1C). In contrast to the pigmentless pksP mutant strain of A. fumigatus, however, similar pigmentless conidia of A. nidulans (wA) still exhibited the ornamentation characteristic of wild-type conidia (Fig. 1D). Taken together, the difference in surface structure between the A. fumigatus pksP mutant and the A. nidulans wA mutant further supports the assumption that different pathways exist for either conidial pigment biosynthesis or pigment deposition in the two species (1). As was noted p...

The new ARCHITECT STAT hs-TnI assay with improved analytical features meets the criteria of high sensitive Tn test and will be a valuable diagnostic tool.

Given the importance of gland morphology in grading prostate cancer (PCa), automatically differentiating between epithelium and other tissues is an important prerequisite for the development of automated methods for detecting PCa. We propose a new deep learning method to segment epithelial tissue in digitised hematoxylin and eosin (H&E) stained prostatectomy slides using immunohistochemistry (IHC) as reference standard. We used IHC to create a precise and objective ground truth compared to manual outlining on H&E slides, especially in areas with high-grade PCa. 102 tissue sections were stained with H&E and subsequently restained with P63 and CK8/18 IHC markers to highlight epithelial structures. Afterwards each pair was co-registered. First, we trained a U-Net to segment epithelial structures in IHC using a subset of the IHC slides that were preprocessed with color deconvolution. Second, this network was applied to the remaining slides to create the reference standard used to train a second U-Net on H&E. Our system accurately segmented both intact glands and individual tumour epithelial cells. The generalisation capacity of our system is shown using an independent external dataset from a different centre. We envision this segmentation as the first part of a fully automated prostate cancer grading pipeline.

Abstract. Infrared limb sounding from aircraft can provide 2-D curtains of multiple trace gas species. However, conventional limb sounders view perpendicular to the aircraft axis and are unable to resolve the observed airmass along their line-of-sight. GLORIA (Gimballed Limb Observer for Radiance Imaging of the Atmosphere) is a new remote sensing instrument that is able to adjust its horizontal view angle with respect to the aircraft flight direction from 45 • to 135 • . This will allow for tomographic measurements of mesoscale structures for a wide variety of atmospheric constituents.Many flights of the GLORIA instrument will not follow closed curves that allow measuring an airmass from all directions. Consequently, it is examined by means of simulations, what spatial resolution can be expected under ideal conditions from tomographic evaluation of measurements made during a straight flight. It is demonstrated that the achievable horizontal resolution in the line-of-sight direction could be reduced from over 200 km to around 70 km compared to conventional retrievals and that the tomographic retrieval is also more robust against horizontal gradients in retrieved quantities in this direction. In a second step, it is shown that the incorporation of channels exhibiting different optical depth can further enhance the spatial resolution of 3-D retrievals enabling the exploitation of spectral samples usually not used for limb sounding due to their opacity.A second problem for tomographic retrievals is that advection, which can be neglected for conventional retrievals, plays an important role for the time-scales involved in a tomographic measurement flight. This paper presents a method to diagnose the effect of a time-varying atmosphere on a 3-D Correspondence to: J. Ungermann (j.ungermann@fz-juelich.de) retrieval and demonstrates an effective way to compensate for effects of advection by incorporating wind-fields from meteorological datasets as a priori information.

This study provides Class III evidence that in patients with AD, oral acitretin increases CSF APPs-α levels.

Our results support previous findings that BMD is subnormal in adults with GHD, that GH replacement therapy can stimulate bone turnover in such adults and that, in the long term, such stimulation results in a significant increase in BMD. In addition they show, for the first time, that BMD may continue to rise even after GH replacement therapy has been administered for 4 years, and indicate that bone elasticity is not adversely affected by long-term GH therapy.