Growth suppressive effect of pegylated arginase in malignant pleural mesothelioma xenografts

BACKGROUND: Malignant pleural mesothelioma (MPM) is a difficult-to-treat global disease. Pegylated arginase (BCT-100) has recently shown anti-tumor effects in hepatocellular carcinoma, acute myeloid leukemia and melanoma. This study aims to investigate the effects of PEG-BCT-100 in MPM. METHODS: A panel of 5 mesothelioma cell lines (H28, 211H, H226, H2052 and H2452) was used to study the in vitro effects of BCT-100 by crystal violet staining. The in vivo effects of BCT-100 were studied using 211H and H226 nude mice xenografts. Protein expression (argininosuccinate synthetase, ornithine transcarbamylase, cleaved PARP, cleaved caspase 3, cyclins (A2, D3, E1 and H), CDK4 and Ki67) and arginine concentration were evaluated by Western blot and ELISA respectively. Cellular localization of BCT-100 was detected by immunohistochemistry and immunoflorescence. TUNEL assay was used to identify cellular apoptotic events. RESULTS: Argininosuccinate synthetase was expressed in H28, H226, and H2452 cells as well as 211H and H266 xenografts. Ornithine transcarbamylase was undetectable in all cell lines and xenograft models. BCT-100 reduced in vitro cell viability (IC50 values at 13-24 mU/ml, 72 h) across different cell lines and suppressed tumor growth in both 211H and H226 xenograft models. BCT-100 (60 mg/kg) significantly suppressed tumor growth (p < 0.01) with prolonged median survival (p < 0.01) in both xenograft models. Combining BCT-100 with pemetrexed or cisplatin conferred no additional benefits over single agents. Serum and intratumoral arginine levels were effectively decreased by BCT-100, associated with cytosolic accumulation of BCT-100 within tumor cells. Apoptosis (PARP cleavage in 211H xenografts; Bcl-2 downregulation, and cleavage of PARP and caspase 3 in H226 xenografts; positive TUNEL staining in both) and G1 arrest (downregulation of cyclin A2, D3, E1 and CDK4 in 211H xenografts; suppression of cyclin A2, E1, H and CDK4 in H226 xenografts) were evident with BCT-100 treatment. Furthermore, proliferative factor Ki67 was downregulated in BCT-100 treatments arms. CONCLUSIONS: BCT-100 suppressed tumor growth with prolonged median survival partially mediated by intratumoral arginine depletion resulting in apoptosis and G1 arrest in mesothelioma xenograft models. The findings provide scientific evidence to support further clinical development of BCT-100 in treatment of MPM.published_or_final_versio

Positive approximations of the inverse of fractional powers of SPD M-matrices

This study is motivated by the recent development in the fractional calculus and its applications. During last few years, several different techniques are proposed to localize the nonlocal fractional diffusion operator. They are based on transformation of the original problem to a local elliptic or pseudoparabolic problem, or to an integral representation of the solution, thus increasing the dimension of the computational domain. More recently, an alternative approach aimed at reducing the computational complexity was developed. The linear algebraic system $\cal A^\alpha \bf u=\bf f$, $0< \alpha <1$ is considered, where $\cal A$ is a properly normalized (scalded) symmetric and positive definite matrix obtained from finite element or finite difference approximation of second order elliptic problems in $\Omega\subset\mathbb{R}^d$, $d=1,2,3$. The method is based on best uniform rational approximations (BURA) of the function $t^{\beta-\alpha}$ for $0 < t \le 1$ and natural $\beta$. The maximum principles are among the major qualitative properties of linear elliptic operators/PDEs. In many studies and applications, it is important that such properties are preserved by the selected numerical solution method. In this paper we present and analyze the properties of positive approximations of $\cal A^{-\alpha}$ obtained by the BURA technique. Sufficient conditions for positiveness are proven, complemented by sharp error estimates. The theoretical results are supported by representative numerical tests

Using Neural Networks for Relation Extraction from Biomedical Literature

Using different sources of information to support automated extracting of relations between biomedical concepts contributes to the development of our understanding of biological systems. The primary comprehensive source of these relations is biomedical literature. Several relation extraction approaches have been proposed to identify relations between concepts in biomedical literature, namely, using neural networks algorithms. The use of multichannel architectures composed of multiple data representations, as in deep neural networks, is leading to state-of-the-art results. The right combination of data representations can eventually lead us to even higher evaluation scores in relation extraction tasks. Thus, biomedical ontologies play a fundamental role by providing semantic and ancestry information about an entity. The incorporation of biomedical ontologies has already been proved to enhance previous state-of-the-art results.Comment: Artificial Neural Networks book (Springer) - Chapter 1

Measuring every particle's size from three-dimensional imaging experiments

Often experimentalists study colloidal suspensions that are nominally monodisperse. In reality these samples have a polydispersity of 4-10%. At the level of an individual particle, the consequences of this polydispersity are unknown as it is difficult to measure an individual particle size from microscopy. We propose a general method to estimate individual particle radii within a moderately concentrated colloidal suspension observed with confocal microscopy. We confirm the validity of our method by numerical simulations of four major systems: random close packing, colloidal gels, nominally monodisperse dense samples, and nominally binary dense samples. We then apply our method to experimental data, and demonstrate the utility of this method with results from four case studies. In the first, we demonstrate that we can recover the full particle size distribution {\it in situ}. In the second, we show that accounting for particle size leads to more accurate structural information in a random close packed sample. In the third, we show that crystal nucleation occurs in locally monodisperse regions. In the fourth, we show that particle mobility in a dense sample is correlated to the local volume fraction.Comment: 7 pages, 5 figure

Heterologous expression screens in Nicotiana benthamiana identify a candidate effector of the wheat Yellow Rust Pathogen that associates with processing bodies

Rust fungal pathogens of wheat (Triticum spp.) affect crop yields worldwide. The molecular mechanisms underlying the virulence of these pathogens remain elusive, due to the limited availability of suitable molecular genetic research tools. Notably, the inability to perform high-throughput analyses of candidate virulence proteins (also known as effectors) impairs progress. We previously established a pipeline for the fast-forward screens of rust fungal candidate effectors in the model plant Nicotiana benthamiana. This pipeline involves selecting candidate effectors in silico and performing cell biology and protein-protein interaction assays in planta to gain insight into the putative functions of candidate effectors. In this study, we used this pipeline to identify and characterize sixteen candidate effectors from the wheat yellow rust fungal pathogen Puccinia striiformis f sp tritici. Nine candidate effectors targeted a specific plant subcellular compartment or protein complex, providing valuable information on their putative functions in plant cells. One candidate effector, PST02549, accumulated in processing bodies (P-bodies), protein complexes involved in mRNA decapping, degradation, and storage. PST02549 also associates with the P-body-resident ENHANCER OF mRNA DECAPPING PROTEIN 4 (EDC4) from N. benthamiana and wheat. We propose that P-bodies are a novel plant cell compartment targeted by pathogen effectors

Characterization of the Major Histocompatibility Complex Class II Genes in Miiuy Croaker

Major histocompatibility complex (MHC) has a central role in the adaptive immune system by presenting foreign peptide to the T-cell receptor. In order to study the molecular function and genomic characteristic of class II genes in teleost, the full lengths of MHC class IIA and IIB cDNA and genomic sequence were cloned from miiuy croaker (Miichthys miiuy). As in other teleost, four exons and three introns were identified in miiuy croaker class IIA gene; but the difference is that six exons and five introns were identified in the miiuy croaker class IIB gene. The deduced amino acid sequence of class IIA and class IIB had 26.3–85.7% and 11.0–88.8% identity with those of mammal and teleost, respectively. Real-time quantitative RT-PCR demonstrated that the MHC class IIA and IIB were ubiquitously expressed in ten normal tissues; expression levels of MHC genes were found first upregulated and then downregulated, and finally by a recovery to normal level throughout the pathogenic bacteria infection process. In addition, we report on the underlying mechanism that maintains sequences diversity among many fish species. A series of site-model tests implemented in the CODEML program revealed that positive Darwinian selection is likely the cause of the molecular evolution in the fish MHC class II genes

Recognising facial expressions in video sequences

We introduce a system that processes a sequence of images of a front-facing human face and recognises a set of facial expressions. We use an efficient appearance-based face tracker to locate the face in the image sequence and estimate the deformation of its non-rigid components. The tracker works in real-time. It is robust to strong illumination changes and factors out changes in appearance caused by illumination from changes due to face deformation. We adopt a model-based approach for facial expression recognition. In our model, an image of a face is represented by a point in a deformation space. The variability of the classes of images associated to facial expressions are represented by a set of samples which model a low-dimensional manifold in the space of deformations. We introduce a probabilistic procedure based on a nearest-neighbour approach to combine the information provided by the incoming image sequence with the prior information stored in the expression manifold in order to compute a posterior probability associated to a facial expression. In the experiments conducted we show that this system is able to work in an unconstrained environment with strong changes in illumination and face location. It achieves an 89\% recognition rate in a set of 333 sequences from the Cohn-Kanade data base

Exact score distribution computation for ontological similarity searches

<p>Abstract</p> <p>Background</p> <p>Semantic similarity searches in ontologies are an important component of many bioinformatic algorithms, e.g., finding functionally related proteins with the Gene Ontology or phenotypically similar diseases with the Human Phenotype Ontology (HPO). We have recently shown that the performance of semantic similarity searches can be improved by ranking results according to the probability of obtaining a given score at random rather than by the scores themselves. However, to date, there are no algorithms for computing the exact distribution of semantic similarity scores, which is necessary for computing the exact <it>P</it>-value of a given score.</p> <p>Results</p> <p>In this paper we consider the exact computation of score distributions for similarity searches in ontologies, and introduce a simple null hypothesis which can be used to compute a <it>P</it>-value for the statistical significance of similarity scores. We concentrate on measures based on Resnik's definition of ontological similarity. A new algorithm is proposed that collapses subgraphs of the ontology graph and thereby allows fast score distribution computation. The new algorithm is several orders of magnitude faster than the naive approach, as we demonstrate by computing score distributions for similarity searches in the HPO. It is shown that exact <it>P</it>-value calculation improves clinical diagnosis using the HPO compared to approaches based on sampling.</p> <p>Conclusions</p> <p>The new algorithm enables for the first time exact <it>P</it>-value calculation via exact score distribution computation for ontology similarity searches. The approach is applicable to any ontology for which the annotation-propagation rule holds and can improve any bioinformatic method that makes only use of the raw similarity scores. The algorithm was implemented in Java, supports any ontology in OBO format, and is available for non-commercial and academic usage under: <url>https://compbio.charite.de/svn/hpo/trunk/src/tools/significance/</url></p

Changes in JC virus-specific T cell responses during natalizumab treatment and in natalizumab-associated progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) induced by JC virus (JCV) is a risk for natalizumab-treated multiple sclerosis (MS) patients. Here we characterize the JCV-specific T cell responses in healthy donors and natalizumab-treated MS patients to reveal functional differences that may account for the development of natalizumab-associated PML. CD4 and CD8 T cell responses specific for all JCV proteins were readily identified in MS patients and healthy volunteers. The magnitude and quality of responses to JCV and cytomegalovirus (CMV) did not change from baseline through several months of natalizumab therapy. However, the frequency of T cells producing IL-10 upon mitogenic stimulation transiently increased after the first dose. In addition, MS patients with natalizumab-associated PML were distinguished from all other subjects in that they either had no detectable JCV-specific T cell response or had JCV-specific CD4 T cell responses uniquely dominated by IL-10 production. Additionally, IL-10 levels were higher in the CSF of individuals with recently diagnosed PML. Thus, natalizumab-treated MS patients with PML have absent or aberrant JCV-specific T cell responses compared with non-PML patients, and changes in T cell-mediated control of JCV replication may be a risk factor for developing PML. Our data suggest further approaches to improved monitoring, treatment and prevention of PML in natalizumab-treated patients