M2Net: Multi-modal Multi-channel Network for Overall Survival Time Prediction of Brain Tumor Patients

Early and accurate prediction of overall survival (OS) time can help to obtain better treatment planning for brain tumor patients. Although many OS time prediction methods have been developed and obtain promising results, there are still several issues. First, conventional prediction methods rely on radiomic features at the local lesion area of a magnetic resonance (MR) volume, which may not represent the full image or model complex tumor patterns. Second, different types of scanners (i.e., multi-modal data) are sensitive to different brain regions, which makes it challenging to effectively exploit the complementary information across multiple modalities and also preserve the modality-specific properties. Third, existing methods focus on prediction models, ignoring complex data-to-label relationships. To address the above issues, we propose an end-to-end OS time prediction model; namely, Multi-modal Multi-channel Network (M2Net). Specifically, we first project the 3D MR volume onto 2D images in different directions, which reduces computational costs, while preserving important information and enabling pre-trained models to be transferred from other tasks. Then, we use a modality-specific network to extract implicit and high-level features from different MR scans. A multi-modal shared network is built to fuse these features using a bilinear pooling model, exploiting their correlations to provide complementary information. Finally, we integrate the outputs from each modality-specific network and the multi-modal shared network to generate the final prediction result. Experimental results demonstrate the superiority of our M2Net model over other methods.Comment: Accepted by MICCAI'2

Alteration of Forkhead Box O (Foxo4) Acetylation Mediates Apoptosis of Podocytes in Diabetes Mellitus

The number of kidney podocytes is reduced in diabetic nephropathy. Advanced glycation end products (AGEs) accumulate in patients with diabetes and promote the apoptosis of podocyte by activating the forkhead box O4 (Foxo4) transcription factor to increase the expression of a pro-apoptosis gene, Bcl2l11. Using chromatin immunoprecipitation we demonstrate that AGE-modified bovine serum albumin (AGE-BSA) enhances Foxo4 binding to a forkhead binding element in the promoter of Bcl2lll. AGE-BSA also increases the acetylation of Foxo4. Lysine acetylation of Foxo4 is required for Foxo4 binding and transcription of Bcl2l11 in podocytes treated with AGE-BSA. The expression of a protein deacetylase that targets Foxo4 for deacetylation, sirtuin (Sirt1), is down regulated in cultured podocytes by AGE-BSA treatment and in glomeruli of diabetic patients. SIRT1 over expression in cultured murine podocytes prevents AGE-induced apoptosis. Glomeruli isolated from diabetic db/db mice have increased acetylation of Foxo4, suppressed expression of Sirt1, and increased expression of Bcl2l11 compared to non-diabetic littermates. Together, our data provide evidence that alteration of Foxo4 acetylation and down regulation of Sirt1 expression in diabetes promote podocyte apoptosis. Strategies to preserve Sirt1 expression or reduce Foxo4 acetylation could be used to prevent podocyte loss in diabetes

Cleavage of the SARS Coronavirus Spike Glycoprotein by Airway Proteases Enhances Virus Entry into Human Bronchial Epithelial Cells In Vitro

Background: Entry of enveloped viruses into host cells requires the activation of viral envelope glycoproteins through cleavage by either intracellular or extracellular proteases. In order to gain insight into the molecular basis of protease cleavage and its impact on the efficiency of viral entry, we investigated the susceptibility of a recombinant native full-length S-protein trimer (triSpike) of the severe acute respiratory syndrome coronavirus (SARS-CoV) to cleavage by various airway proteases. Methodology/Principal Findings: Purified triSpike proteins were readily cleaved in vitro by three different airway proteases: trypsin, plasmin and TMPRSS11a. High Performance Liquid Chromatography (HPLC) and amino acid sequencing analyses identified two arginine residues (R667 and R797) as potential protease cleavage site(s). The effect of protease-dependent enhancement of SARS-CoV infection was demonstrated with ACE2 expressing human bronchial epithelial cells 16HBE. Airway proteases regulate the infectivity of SARS-CoV in a fashion dependent on previous receptor binding. The role of arginine residues was further shown with mutant constructs (R667A, R797A or R797AR667A). Mutation of R667 or R797 did not affect the expression of S-protein but resulted in a differential efficacy of pseudotyping into SARS-CoVpp. The R667A SARS-CoVpp mutant exhibited a lack of virus entry enhancement following protease treatment. Conclusions/Significance: These results suggest that SARS S-protein is susceptible to airway protease cleavage and, furthermore, that protease mediated enhancement of virus entry depends on specific conformation of SARS S-protein upon ACE2 binding. These data have direct implications for the cell entry mechanism of SARS-CoV along the respiratory system and, furthermore expand the possibility of identifying potential therapeutic agents against SARS-CoV. © 2009 Kam et al.published_or_final_versio

Identification of molecular pathways affected by pterostilbene, a natural dimethylether analog of resveratrol

<p>Abstract</p> <p>Background</p> <p>Pterostilbene, a naturally occurring phenolic compound produced by agronomically important plant genera such as <it>Vitis </it>and <it>Vacciunium</it>, is a phytoalexin exhibiting potent antifungal activity. Additionally, recent studies have demonstrated several important pharmacological properties associated with pterostilbene. Despite this, a systematic study of the effects of pterostilbene on eukaryotic cells at the molecular level has not been previously reported. Thus, the aim of the present study was to identify the cellular pathways affected by pterostilbene by performing transcript profiling studies, employing the model yeast <it>Saccharomyces cerevisiae</it>.</p> <p>Methods</p> <p><it>S. cerevisiae </it>strain S288C was exposed to pterostilbene at the IC₅₀concentration (70 μM) for one generation (3 h). Transcript profiling experiments were performed on three biological replicate samples using the Affymetrix GeneChip Yeast Genome S98 Array. The data were analyzed using the statistical methods available in the GeneSifter microarray data analysis system. To validate the results, eleven differentially expressed genes were further examined by quantitative real-time RT-PCR, and <it>S. cerevisiae </it>mutant strains with deletions in these genes were analyzed for altered sensitivity to pterostilbene.</p> <p>Results</p> <p>Transcript profiling studies revealed that pterostilbene exposure significantly down-regulated the expression of genes involved in methionine metabolism, while the expression of genes involved in mitochondrial functions, drug detoxification, and transcription factor activity were significantly up-regulated. Additional analyses revealed that a large number of genes involved in lipid metabolism were also affected by pterostilbene treatment.</p> <p>Conclusion</p> <p>Using transcript profiling, we have identified the cellular pathways targeted by pterostilbene, an analog of resveratrol. The observed response in lipid metabolism genes is consistent with its known hypolipidemic properties, and the induction of mitochondrial genes is consistent with its demonstrated role in apoptosis in human cancer cell lines. Furthermore, our data show that pterostilbene has a significant effect on methionine metabolism, a previously unreported effect for this compound.</p

Sexual dimorphism in cancer.

The incidence of many types of cancer arising in organs with non-reproductive functions is significantly higher in male populations than in female populations, with associated differences in survival. Occupational and/or behavioural factors are well-known underlying determinants. However, cellular and molecular differences between the two sexes are also likely to be important. In this Opinion article, we focus on the complex interplay that sex hormones and sex chromosomes can have in intrinsic control of cancer-initiating cell populations, the tumour microenvironment and systemic determinants of cancer development, such as the immune system and metabolism. A better appreciation of these differences between the two sexes could be of substantial value for cancer prevention as well as treatment

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Automated Glioblastoma Segmentation Based on a Multiparametric Structured Unsupervised Classification

Automatic brain tumour segmentation has become a key component for the future of brain tumour treatment. Currently, most of brain tumour segmentation approaches arise from the supervised learning standpoint, which requires a labelled training dataset from which to infer the models of the classes. The performance of these models is directly determined by the size and quality of the training corpus, whose retrieval becomes a tedious and time-consuming task. On the other hand, unsupervised approaches avoid these limitations but often do not reach comparable results than the supervised methods. In this sense, we propose an automated unsupervised method for brain tumour segmentation based on anatomical Magnetic Resonance (MR) images. Four unsupervised classification algorithms, grouped by their structured or non-structured condition, were evaluated within our pipeline. Considering the non-structured algorithms, we evaluated K-means, Fuzzy K-means and Gaussian Mixture Model (GMM), whereas as structured classification algorithms we evaluated Gaussian Hidden Markov Random Field (GHMRF). An automated postprocess based on a statistical approach supported by tissue probability maps is proposed to automatically identify the tumour classes after the segmentations. We evaluated our brain tumour segmentation method with the public BRAin Tumor Segmentation (BRATS) 2013 Test and Leaderboard datasets. Our approach based on the GMM model improves the results obtained by most of the supervised methods evaluated with the Leaderboard set and reaches the second position in the ranking. Our variant based on the GHMRF achieves the first position in the Test ranking of the unsupervised approaches and the seventh position in the general Test ranking, which confirms the method as a viable alternative for brain tumour segmentation.EFG was supported by Programa Torres Quevedo, Ministerio de Educacion y Ciencia, co-funded by the European Social Fund (PTQ-1205693). EFG, JMGG, and JVM were supported by Red Tematica de Investigacion Cooperativa en Cancer, (RTICC) 2013-2016 (RD12/0036/0020). JMGG was supported by Project TIN2013-43457-R: Caracterizacion de firmas biologicas de glioblastomas mediante modelos no-supervisados de prediccion estructurada basados en biomarcadores de imagen, co-funded by the Ministerio de Economia y Competitividad of Spain; CON2014001 UPV-IISLaFe: Unsupervised glioblastoma tumor components segmentation based on perfusion multiparametric MRI and spatio/temporal constraints; and CON2014002 UPV-IISLaFe: Empleo de segmentacion no supervisada multiparametrica basada en perfusion RM para la caracterizacion del edema peritumoral de gliomas y metastasis cerebrales unicas, funded by Instituto de Investigacion Sanitaria H. Universitario y Politecnico La Fe. This work was partially supported by the Instituto de Aplicaciones de las Tecnologias de la Informacion y las Comunicaciones Avanzadas (ITACA). Veratech for Health S.L. provided support in the form of salaries for author EF-G, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author is articulated in the "author contributions" section. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.Juan Albarracín, J.; Fuster García, E.; Manjón Herrera, JV.; Robles Viejo, M.; Aparici, F.; Marti-Bonmati, L.; García Gómez, JM. (2015). Automated Glioblastoma Segmentation Based on a Multiparametric Structured Unsupervised Classification. PLoS ONE. 10(5):1-20. https://doi.org/10.1371/journal.pone.0125143S120105Wen, P. Y., Macdonald, D. R., Reardon, D. A., Cloughesy, T. F., Sorensen, A. G., Galanis, E., … Chang, S. M. (2010). Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group. Journal of Clinical Oncology, 28(11), 1963-1972. doi:10.1200/jco.2009.26.3541Bauer, S., Wiest, R., Nolte, L.-P., & Reyes, M. (2013). A survey of MRI-based medical image analysis for brain tumor studies. Physics in Medicine and Biology, 58(13), R97-R129. doi:10.1088/0031-9155/58/13/r97Dolecek, T. A., Propp, J. M., Stroup, N. E., & Kruchko, C. (2012). CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2005-2009. Neuro-Oncology, 14(suppl 5), v1-v49. doi:10.1093/neuonc/nos218Gordillo, N., Montseny, E., & Sobrevilla, P. (2013). State of the art survey on MRI brain tumor segmentation. Magnetic Resonance Imaging, 31(8), 1426-1438. doi:10.1016/j.mri.2013.05.002Verma, R., Zacharaki, E. I., Ou, Y., Cai, H., Chawla, S., Lee, S.-K., … Davatzikos, C. (2008). Multiparametric Tissue Characterization of Brain Neoplasms and Their Recurrence Using Pattern Classification of MR Images. Academic Radiology, 15(8), 966-977. doi:10.1016/j.acra.2008.01.029Jensen, T. R., & Schmainda, K. M. (2009). Computer-aided detection of brain tumor invasion using multiparametric MRI. Journal of Magnetic Resonance Imaging, 30(3), 481-489. doi:10.1002/jmri.21878Breiman, L. (2001). Machine Learning, 45(1), 5-32. doi:10.1023/a:1010933404324Wagstaff KL. Intelligent Clustering with instance-level constraints. PhD Thesis, Cornell University. 2002.Fletcher-Heath, L. M., Hall, L. O., Goldgof, D. B., & Murtagh, F. R. (2001). Automatic segmentation of non-enhancing brain tumors in magnetic resonance images. Artificial Intelligence in Medicine, 21(1-3), 43-63. doi:10.1016/s0933-3657(00)00073-7Nie, J., Xue, Z., Liu, T., Young, G. S., Setayesh, K., Guo, L., & Wong, S. T. C. (2009). Automated brain tumor segmentation using spatial accuracy-weighted hidden Markov Random Field. Computerized Medical Imaging and Graphics, 33(6), 431-441. doi:10.1016/j.compmedimag.2009.04.006Zhu, Y., Young, G. S., Xue, Z., Huang, R. Y., You, H., Setayesh, K., … Wong, S. T. (2012). Semi-Automatic Segmentation Software for Quantitative Clinical Brain Glioblastoma Evaluation. Academic Radiology, 19(8), 977-985. doi:10.1016/j.acra.2012.03.026Zhang, Y., Brady, M., & Smith, S. (2001). Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE Transactions on Medical Imaging, 20(1), 45-57. doi:10.1109/42.906424Vijayakumar, C., Damayanti, G., Pant, R., & Sreedhar, C. M. (2007). Segmentation and grading of brain tumors on apparent diffusion coefficient images using self-organizing maps. Computerized Medical Imaging and Graphics, 31(7), 473-484. doi:10.1016/j.compmedimag.2007.04.004Prastawa, M., Bullitt, E., Moon, N., Van Leemput, K., & Gerig, G. (2003). Automatic brain tumor segmentation by subject specific modification of atlas priors1. Academic Radiology, 10(12), 1341-1348. doi:10.1016/s1076-6332(03)00506-3Gudbjartsson, H., & Patz, S. (1995). The rician distribution of noisy mri data. Magnetic Resonance in Medicine, 34(6), 910-914. doi:10.1002/mrm.1910340618Buades, A., Coll, B., & Morel, J. M. (2005). A Review of Image Denoising Algorithms, with a New One. Multiscale Modeling & Simulation, 4(2), 490-530. doi:10.1137/040616024Manjón, J. V., Coupé, P., Martí-Bonmatí, L., Collins, D. L., & Robles, M. (2009). Adaptive non-local means denoising of MR images with spatially varying noise levels. Journal of Magnetic Resonance Imaging, 31(1), 192-203. doi:10.1002/jmri.22003Sled, J. G., Zijdenbos, A. P., & Evans, A. C. (1998). A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Transactions on Medical Imaging, 17(1), 87-97. doi:10.1109/42.668698Tustison, N. J., Avants, B. B., Cook, P. A., Yuanjie Zheng, Egan, A., Yushkevich, P. A., & Gee, J. C. (2010). N4ITK: Improved N3 Bias Correction. IEEE Transactions on Medical Imaging, 29(6), 1310-1320. doi:10.1109/tmi.2010.2046908Manjón, J. V., Coupé, P., Buades, A., Collins, D. L., & Robles, M. (2010). MRI Superresolution Using Self-Similarity and Image Priors. International Journal of Biomedical Imaging, 2010, 1-11. doi:10.1155/2010/425891Rousseau, F. (2010). A non-local approach for image super-resolution using intermodality priors☆. Medical Image Analysis, 14(4), 594-605. doi:10.1016/j.media.2010.04.005Protter, M., Elad, M., Takeda, H., & Milanfar, P. (2009). Generalizing the Nonlocal-Means to Super-Resolution Reconstruction. IEEE Transactions on Image Processing, 18(1), 36-51. doi:10.1109/tip.2008.2008067Manjón, J. V., Coupé, P., Buades, A., Fonov, V., Louis Collins, D., & Robles, M. (2010). Non-local MRI upsampling. Medical Image Analysis, 14(6), 784-792. doi:10.1016/j.media.2010.05.010Kassner, A., & Thornhill, R. E. (2010). Texture Analysis: A Review of Neurologic MR Imaging Applications. American Journal of Neuroradiology, 31(5), 809-816. doi:10.3174/ajnr.a2061Ahmed, S., Iftekharuddin, K. M., & Vossough, A. (2011). Efficacy of Texture, Shape, and Intensity Feature Fusion for Posterior-Fossa Tumor Segmentation in MRI. IEEE Transactions on Information Technology in Biomedicine, 15(2), 206-213. doi:10.1109/titb.2011.2104376Lloyd, S. (1982). Least squares quantization in PCM. IEEE Transactions on Information Theory, 28(2), 129-137. doi:10.1109/tit.1982.1056489Dunn, J. C. (1973). A Fuzzy Relative of the ISODATA Process and Its Use in Detecting Compact Well-Separated Clusters. Journal of Cybernetics, 3(3), 32-57. doi:10.1080/01969727308546046Bezdek, J. C. (1981). Pattern Recognition with Fuzzy Objective Function Algorithms. doi:10.1007/978-1-4757-0450-1Hammersley, JM, Clifford, P. Markov fields on finite graphs and lattices. 1971.Komodakis, N., & Tziritas, G. (2007). Approximate Labeling via Graph Cuts Based on Linear Programming. IEEE Transactions on Pattern Analysis and Machine Intelligence, 29(8), 1436-1453. doi:10.1109/tpami.2007.1061Komodakis, N., Tziritas, G., & Paragios, N. (2008). Performance vs computational efficiency for optimizing single and dynamic MRFs: Setting the state of the art with primal-dual strategies. Computer Vision and Image Understanding, 112(1), 14-29. doi:10.1016/j.cviu.2008.06.007Fonov, V., Evans, A. C., Botteron, K., Almli, C. R., McKinstry, R. C., & Collins, D. L. (2011). Unbiased average age-appropriate atlases for pediatric studies. NeuroImage, 54(1), 313-327. doi:10.1016/j.neuroimage.2010.07.033Fonov, V., Evans, A., McKinstry, R., Almli, C., & Collins, D. (2009). Unbiased nonlinear average age-appropriate brain templates from birth to adulthood. NeuroImage, 47, S102. doi:10.1016/s1053-8119(09)70884-5Klein, A., Andersson, J., Ardekani, B. A., Ashburner, J., Avants, B., Chiang, M.-C., … Parsey, R. V. (2009). Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration. NeuroImage, 46(3), 786-802. doi:10.1016/j.neuroimage.2008.12.037AVANTS, B., EPSTEIN, C., GROSSMAN, M., & GEE, J. (2008). Symmetric diffeomorphic image registration with cross-correlation: Evaluating automated labeling of elderly and neurodegenerative brain. Medical Image Analysis, 12(1), 26-41. doi:10.1016/j.media.2007.06.004Saez C, Robles M, Garcia-Gomez JM. Stability metrics for multi-source biomedical data based on simplicial projections from probability distribution distances. Statistical Methods in Medical Research 2014; In press

A computational framework for complex disease stratification from multiple large-scale datasets.

BACKGROUND: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine