The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target

Malignant mesothelioma (MM) is a highly aggressive cancer with limited therapeutic options. We have previously shown that the endocytic collagen receptor, uPARAP, is upregulated in certain cancers and can be therapeutically targeted. Public RNA expression data display uPARAP overexpression in MM. Thus, to evaluate its potential use in diagnostics and therapy, we quantified uPARAP expression by immunohistochemical H-score in formalin-fixed paraffin-embedded bioptic/surgical human tissue samples and tissue microarrays. We detected pronounced upregulation of uPARAP in the three main MM subtypes compared to non-malignant reactive mesothelial proliferations, with higher expression in sarcomatoid and biphasic than in epithelioid MM. The upregulation appeared to be independent of patients’ asbestos exposure and unaffected after chemotherapy. Using immunoblotting, we demonstrated high expression of uPARAP in MM cell lines and no expression in a non-malignant mesothelial cell line. Moreover, we showed the specific internalization of an anti-uPARAP monoclonal antibody by the MM cell lines using flow cytometry-based assays and confocal microscopy. Finally, we demonstrated the sensitivity of these cells towards sub-nanomolar concentrations of an antibody-drug conjugate formed with the uPARAP-directed antibody and a potent cytotoxin that led to efficient, uPARAP-specific eradication of the MM cells. Further studies on patient cohorts and functional preclinical models will fully reveal whether uPARAP could be exploited in diagnostics and therapeutic targeting of MM.     

Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in Shb-Deficient Endothelial Cells Increases Tumor Lung Metastasis

Metastasis reflects both the inherent properties of tumor cells and the response of the stroma to the presence of the tumor. Vascular barrier properties, either due to endothelial cell (EC) or pericyte function, play an important role in metastasis in addition to the contribution of the immune system. The Shb gene encodes the Src homology-2 domain protein B that operates downstream of tyrosine kinases in both vascular and immune cells. We have investigated E0771.lmb breast carcinoma metastasis in mice with conditional deletion of the Shb gene using the Cdh5-Cre^ERt2 transgene, resulting in inactivation of the Shb-gene in EC and some hematopoietic cell populations. Lung metastasis from orthotopic tumors, tumor vascular and immune cell characteristics, and immune cell gene expression profiles were determined. We found no increase in vascular leakage that could explain the observed increase in metastasis upon the loss of Shb expression. Instead, Shb deficiency in EC promoted the recruitment of monocytic/macrophagic myeloid-derived suppressor cells (mMDSC), an immune cell type that confers a suppressive immune response, thus enhancing lung metastasis. An MDSC-promoting cytokine/chemokine profile was simultaneously observed in tumors grown in mice with EC-specific Shb deficiency, providing an explanation for the expanded mMDSC population. The results demonstrate an intricate interplay between tumor EC and immune cells that pivots between pro-tumoral and anti-tumoral properties, depending on relevant genetic and/or environmental factors operating in the microenvironment.     

Comparison of irreversible deformation and yielding in microlayers of polycarbonate with poly(methylmethacrylate) and poly(styrene‐co‐acrylonitrile)

Microlayers of polycarbonate (PC) with poly(methylmethacrylate) (PMMA) or poly(styrene‐co‐acrylonitrile) (SAN) were processed with varying layer thicknesses. Adhesion between PC and PMMA was found to be an order of magnitude higher than between PC and SAN, as determined with the T‐peel method. To probe the effect of the adhesion difference on yielding and deformation of PC/PMMA and PC/SAN microlayers, the macroscopic stress–strain behavior was examined as a function of layer thickness and strain rate, and the results were interpreted in terms of the microdeformation behavior. During yielding, crazes in thick SAN layers opened up into cracks; however, PC layers drew easily because local delamination relieved constraint at the PC/SAN interface. Adhesion of PC/PMMA was too strong for delamination at the interface when PMMA crazes opened up into cracks at low strain rates. Instead, PMMA cracks tore into neighboring PC layers and initiated fracture. At higher strain rates, good adhesion produced yielding of thick PMMA layers, a phenomenon not observed with thick SAN layers. The change in microdeformation mechanism of PMMA with increasing strain rate produced a transition in the yield stress of PC/PMMA microlayers. Microlayers of both PC/SAN and PC/PMMA with thinner layers (individual layers 0.3–0.6 μm thick) exhibited improved ballistic performance compared to microlayers with thicker layers (individual layers 10–20 μm thick), which was due to cooperative yielding of both components. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 77: 1545–1557, 2000     

The Cost of Complex Communication on Simple Networks

Endowing a communication network with the ability to realize arbitrary communication patterns is an expensive proposition, both in hardware and in system software. One might instead ask whether, for a given application program, a simple network can be built that performs well for that particular program. In this paper, we model an application program by the set of communication patterns it uses. We then consider the problem of determining when such a set of communication patterns is suitable for fast realization on a simple network. We show that the question of whether there exists a simple, inexpensive network for an algorithm is closely related to the VLSI layout question. In particular, we show how the VLSI framework can be used to produce a simple test that tells how complex such a network must be. Within this context we show that, contrary to common wisdom, the communication necessary for block-matrix transpose does not require complex hardware—in fact, it is efficiently realizable on a mesh. However, other important patterns, such as perfect shuffle, do indeed require either expensive hardware or large amounts of message congestion.     

Time-varying reconstruction of the ionosphere. 1. The algorithm

Total electron content data can be used to reconstruct images of ionospheric electron density using computed ionospheric tomography (CIT). All existing CIT algorithms are formulated with the assumption that the ionosphere does not move during data collection. Since existing algorithms are static reconstruction algorithms, the motion of the ionosphere becomes a source of image degradation. This article presents a time-varying CIT algorithm that reconstructs several time slices of the ionosphere instead of a single static image. Thus, the new algorithm is not adversely affected by the motion of the ionosphere. The new algorithm uses a priori information on the vertical distribution of ionospheric electron density, but no a priori information on ionospheric motion, so the motion is reconstructed solely on the basis of information contained in the data. © 1998 John Wiley & Sons, Inc. Int J Imaging Syst Technol 9: 484–490, 1998     

Transposable Prophages in Leptospira: An Ancient,Now Diverse,Group Predominant in Causative Agents of Weil’s Disease

The virome associated with the corkscrew shaped bacterium Leptospira, responsible for Weil’s disease, is scarcely known, and genetic tools available for these bacteria remain limited. To reduce these two issues, potential transposable prophages were searched in Leptospiraceae genomes. The 236 predicted transposable prophages were particularly abundant in the most pathogenic leptospiral clade, being potentially involved in the acquisition of virulent traits. According to genomic similarities and phylogenies, these prophages are distantly related to known transposable phages and are organized into six groups, one of them encompassing prophages with unusual TA-TA ends. Interestingly, structural and transposition proteins reconstruct different relationships between groups, suggesting ancestral recombinations. Based on the baseplate phylogeny, two large clades emerge, with specific gene-contents and high sequence divergence reflecting their ancient origin. Despite their high divergence, the size and overall genomic organization of all prophages are very conserved, a testimony to the highly constrained nature of their genomes. Finally, similarities between these prophages and the three known non-transposable phages infecting L. biflexa, suggest gene transfer between different Caudovirales inside their leptospiral host, and the possibility to use some of the transposable prophages in that model strain.     

The Progress of Intestinal Epithelial Models from Cell Lines to Gut-On-Chip

Over the past years, several preclinical in vitro and ex vivo models have been developed that helped to understand some of the critical aspects of intestinal functions in health and disease such as inflammatory bowel disease (IBD). However, the translation to the human in vivo situation remains problematic. The main reason for this is that these approaches fail to fully reflect the multifactorial and complex in vivo environment (e.g., including microbiota, nutrition, and immune response) in the gut system. Although conventional models such as cell lines, Ussing chamber, and the everted sac are still used, increasingly more sophisticated intestinal models have been developed over the past years including organoids, InTESTine™ and microfluidic gut-on-chip. In this review, we gathered the most recent insights on the setup, advantages, limitations, and future perspectives of most frequently used in vitro and ex vivo models to study intestinal physiology and functions in health and disease.     

Bioreactor and probe system for magnetic resonance microimaging and spectroscopy of chondrocytes and neocartilage

We have developed a nuclear magnetic resonance (NMR)-compatible hollow fiber chondrocyte bioreactor (HFBR), permitting the noninvasive study of neocartilage under conditions optimized for cell growth and matrix expression. The system was used to investigate the properties of neocartilage which developed from embryonic chick chondrocytes. Histologic studies performed 30 days after inoculation of the HFBR with chondrocytes showed cartilage growth units demarcated by stromal layers surrounding each fiber; the tissue itself was highly cellular with abundant proteoglycan content. Spin-density, spin-lattice, and spin-spin relaxation and magnetization transfer contrast images revealed heterogeneous tissue with NMR properties that correlated well with histologic data. It was found that the apparent free water content of the neocartilage was greater than that seen in mature cartilage, even in regions of relatively low cell density. The bioenergetic profile of the cells in culture was monitored with ³¹P-NMR spectroscopy, and the presence of phosphocreatine was clearly demonstrated. Overall metabolic stability was confirmed between days 10 and 17 after inoculation. A significant decrease in intracellular pH with time was observed during early development of the chondrocyte system. © 1997 John Wiley & Sons, Inc. Int J Imaging Syst Technol, 8, 285–292, 1997     

Variable structure tracking control of a single‐link flexible arm using time‐varying sliding surface

In this article, a novel variable structure controller has been developed for the trajectory tracking of a one‐link flexible arm. The controller consists of two sliding surfaces: namely, a three‐term time invariant surface for the hub angle and a two‐term time varying surface for the first vibration mode of the arm. Switching control laws are obtained analytically so as to guarantee the global stability as well as the attractiveness toward the two sliding surfaces. The lowest allowable sampling frequency for digital implementation is also derived. Experiments are performed on a one‐link flexible arm and results demonstrate the effectiveness of the proposed controller. ©1999 John Wiley & Sons, Inc.