Prevention of colitis-associated colon cancer using a vaccine to target abnormal expression of the MUC1 tumor antigen

Association between chronic inflammation and cancer development is exemplified by inflammatory bowel disease (IBD) where patients with chronic uncontrolled colitis have a significantly increased risk of developing colitis-associated colorectal cancer (CACC). CACC appears to progresses through the inflammation-dysplasia-carcinoma sequence. This highlights the need to identify targets and interventions that reduce inflammation and prevent development of dysplasia in the context of IBD. Using the dextran sulfate sodium (DSS) mouse model of chronic colitis and CACC, we show that an important target of intervention in human disease would be the epithelial cell molecule MUC1 that is aberrantly expressed on inflamed colonocytes and promotes inflammation and progression to CACC. We show that a MUC1 vaccine can ameliorate chronic colitis and prevent development of dysplasia in the colon and thus extend survival in human MUC1 transgenic mice. This study supports the potential of prophylactic vaccines to target antigens that become aberrantly expressed in chronic inflammation (e.g., IBD) and continue to be expressed on the associated cancers (e.g., colon cancer), to prevent and/or treat both diseases

Topological Homogeneity for Electron Microscopy Images

In this paper, the concept of homogeneity is defined, from a topological perspective, in order to analyze how uniform is the material composition in 2D electron microscopy images. Topological multiresolution parameters are taken into account to obtain better results than classical techniques.Ministerio de Economía y Competitividad MTM2016-81030-PMinisterio de Economía y Competitividad TEC2012-37868-C04-0

Transcriptome analysis reveals differential splicing events in IPF lung tissue

Idiopathic pulmonary fibrosis (IPF) is a complex disease in which a multitude of proteins and networks are disrupted. Interrogation of the transcriptome through RNA sequencing (RNA-Seq) enables the determination of genes whose differential expression is most significant in IPF, as well as the detection of alternative splicing events which are not easily observed with traditional microarray experiments. We sequenced messenger RNA from 8 IPF lung samples and 7 healthy controls on an Illumina HiSeq 2000, and found evidence for substantial differential gene expression and differential splicing. 873 genes were differentially expressed in IPF (FDR<5%), and 440 unique genes had significant differential splicing events in at least one exonic region (FDR<5%). We used qPCR to validate the differential exon usage in the second and third most significant exonic regions, in the genes COL6A3 (RNA-Seq adjusted pval = 7.18e-10) and POSTN (RNA-Seq adjusted pval = 2.06e-09), which encode the extracellular matrix proteins collagen alpha-3(VI) and periostin. The increased gene-level expression of periostin has been associated with IPF and its clinical progression, but its differential splicing has not been studied in the context of this disease. Our results suggest that alternative splicing of these and other genes may be involved in the pathogenesis of IPF. We have developed an interactive web application which allows users to explore the results of our RNA-Seq experiment, as well as those of two previously published microarray experiments, and we hope that this will serve as a resource for future investigations of gene regulation in IPF. © 2014 Nance et al

Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin-Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic syndrome characterized by sudden death. There are several genetic forms of CPVT associated with mutations in genes encoding the cardiac ryanodine receptor (RyR2) and its auxiliary proteins including calsequestrin (CASQ2) and calmodulin (CaM). It has been suggested that impairment of the ability of RyR2 to stay closed (ie, refractory) during diastole may be a common mechanism for these diseases. Here, we explore the possibility of engineering CaM variants that normalize abbreviated RyR2 refractoriness for subsequent viral-mediated delivery to alleviate arrhythmias in non-CaM-related CPVT. METHODS AND RESULTS: To that end, we have designed a CaM protein (GSH-M37Q; dubbed as therapeutic CaM or T-CaM) that exhibited a slowed N-terminal Ca dissociation rate and prolonged RyR2 refractoriness in permeabilized myocytes derived from CPVT mice carrying the CASQ2 mutation R33Q. This T-CaM was introduced to the heart of R33Q mice through recombinant adeno-associated viral vector serotype 9. Eight weeks postinfection, we performed confocal microscopy to assess Ca handling and recorded surface ECGs to assess susceptibility to arrhythmias in vivo. During catecholamine stimulation with isoproterenol, T-CaM reduced isoproterenol-promoted diastolic Ca waves in isolated CPVT cardiomyocytes. Importantly, T-CaM exposure abolished ventricular tachycardia in CPVT mice challenged with catecholamines. CONCLUSIONS: Our results suggest that gene transfer of T-CaM by adeno-associated viral vector serotype 9 improves myocyte Ca handling and alleviates arrhythmias in a calsequestrin-associated CPVT model, thus supporting the potential of a CaM-based antiarrhythmic approach as a therapeutic avenue for genetically distinct forms of CPV

Cis and Trans Effects of Human Genomic Variants on Gene Expression

This work was funded by the Louis-Jeantet Foundation (http://www.jeantet.ch/), the European Research Council (Grant ID: 260927 http://erc.europa.eu/), the Swiss National Foundation (Grant ID: 130342 http://www.snf.ch), NCCR Frontiers In Genetics (http://www.frontiers-in-genetics.org), the UK Medical Research Council (http://www.mrc.ac.uk) and the Wellcome Trust (Grant ID: 092731).

Microalgae production in fresh market wastewater and its utilization as a protein substitute in formulated fish feed for oreochromis spp.

Rapid growing of human population has led to increasing demand of aquaculture production. Oreochromis niloticus or known as tilapia is one of the most globally cultured freshwater fish due to its great adaptation towards extreme environment. Besides, farming of tilapia not only involves small scales farming for local consumption but also larger scales for international market which contributes to a foreign currency earning. Extensive use of fishmeal as feed for fish and for other animals indirectly caused an increasing depletion of the natural resource and may consequently cause economic and environmental unstable. Microalgae biomass seems to be a promising feedstock in aquaculture industry. It can be used for many purposes such as live food for fish larvae and dried microalgae to substitute protein material in fish feed. The microalgae replacement in fish feed formulation as protein alternative seem potentially beneficial for long term aqua-business sustainability. The present chapter discussed the potential of microalgae as an alternative nutrition in fish feed formulations, specifically Tilapia

Humoral immune response to MUC5AC in patients with colorectal polyps and colorectal carcinoma

BACKGROUND: MUC5AC is a secreted mucin aberrantly expressed by colorectal polyps and carcinoma. It has been hypothesized that aberrant expression of MUC5AC in colorectal carcinoma tissues increased the overall survival of patients with colorectal carcinoma. The present study investigates the incidence of naturally occurring MUC5AC antibodies in the sera of normal individuals, patients with colonic polyps and patients with advanced colorectal carcinoma. A second aim was to determine the relationship of MUC5AC antibody with the prognosis of colorectal carcinoma. METHODS: Free circulating MUC5AC antibodies were measured using an enzyme-linked immunosorbent assay with a synthetic peptide corresponding to an 8 aa. segment of MUC5AC tandem repeat region. Immunohistochemical analysis was completed to demonstrate MUC5AC expression in the polyp specimens. RESULTS: MUC5AC antibodies were detected in 6 of 22 (27.3%) healthy subjects, 9 of 20 (45%) polyp patients, 18 of 30 (60%) patients with colorectal cancer. The presence of circulating free MUC5AC antibody levels was significantly correlated with expression of MUC5AC in polyp sections. Serum MUC5AC antibody positivity was higher in patients with colon located tumors, advanced stage and poorly differentiated tumors were found negatively affecting patient survival in our study. MUC5AC antibody positivity was higher in patients with poor prognostic parameters. Disease free survival and overall survival were shorter in this group of patients. In the multivariate analysis MUC5AC antibody positivity didn't find an independent prognostic factor on prognosis. CONCLUSION: Decreased survival in colorectal carcinoma patients with MUC5AC antibody positivity may be due to a decrease in the MUC5AC expression in tumor tissues of surviving carcinoma patients