280 research outputs found

    Non-coding regions of nuclear-DNA-encoded mitochondrial genes and intergenic sequences are targeted by autoantibodies in breast cancer

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    Autoantibodies against mitochondrial-derived antigens play a key role in chronic tissue inflammation in autoimmune disorders and cancers. Here, we identify autoreactive nuclear genomic DNA (nDNA)-encoded mitochondrial gene products (GAPDH, PKM2, GSTP1, SPATA5, MFF, TSPOAP1, PHB2, COA4, and HAGH) recognized by breast cancer (BC) patients\u27 sera as nonself, supporting a direct relationship of mitochondrial autoimmunity to breast carcinogenesis. Autoreactivity of multiple nDNA-encoded mitochondrial gene products was mapped to protein-coding regions, 3\u27 untranslated regions (UTRs), as well as introns. In addition, autoantibodies in BC sera targeted intergenic sequences that may be parts of long non-coding RNA (lncRNA) genes, including LINC02381 and other putative lncRNA neighbors of the protein-coding genes ERCC4, CXCL13, SOX3, PCDH1, EDDM3B, and GRB2. Increasing evidence indicates that lncRNAs play a key role in carcinogenesis. Consistent with this, our findings suggest that lncRNAs, as well as mRNAs of nDNA-encoded mitochondrial genes, mechanistically contribute to BC progression. This work supports a new paradigm of breast carcinogenesis based on a globally dysfunctional genome with altered function of multiple mitochondrial and non-mitochondrial oncogenic pathways caused by the effects of autoreactivity-induced dysregulation of multiple genes and their products. This autoimmunity-based model of carcinogenesis will open novel avenues for BC treatment

    Elucidating the mitochondrial proteome of Toxoplasma gondii reveals the presence of a divergent cytochrome c oxidase

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    The mitochondrion of apicomplexan parasites is critical for parasite survival, although the full complement of proteins that localize to this organelle has not been defined. Here we undertake two independent approaches to elucidate the mitochondrial proteome of the apicomplexan Toxoplasma gondii. We identify approximately 400 mitochondrial proteins, many of which lack homologs in the animals that these parasites infect, and most of which are important for parasite growth. We demonstrate that one such protein, termed TgApiCox25, is an important component of the parasite cytochrome c oxidase (COX) complex. We identify numerous other apicomplexan-specific components of COX, and conclude that apicomplexan COX, and apicomplexan mitochondria more generally, differ substantially in their protein composition from the hosts they infect. Our study highlights the diversity that exists in mitochondrial proteomes across the eukaryotic domain of life, and provides a foundation for defining unique aspects of mitochondrial biology in an important phylum of parasites.This work was supported by a Discovery Grant and QEII fellowship from the Australian Research Council (ARC DP110103144) to GvD

    Mechanisms of mitochondrial promoter recognition in humans and other mammalian species

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    Recognition of mammalian mitochondrial promoters requires the concerted action of mitochondrial RNA polymerase (mtRNAP) and transcription initiation factors TFAM and TFB2M. In this work, we found that transcript slippage results in heterogeneity of the human mitochondrial transcripts in vivo and in vitro. This allowed us to correctly interpret the RNAseq data, identify the bona fide transcription start sites (TSS), and assign mitochondrial promoters for \u3e 50% of mammalian species and some other vertebrates. The divergent structure of the mammalian promoters reveals previously unappreciated aspects of mtDNA evolution. The correct assignment of TSS also enabled us to establish the precise register of the DNA in the initiation complex and permitted investigation of the sequence-specific protein-DNA interactions. We determined the molecular basis of promoter recognition by mtRNAP and TFB2M, which cooperatively recognize bases near TSS in a species-specific manner. Our findings reveal a role of mitochondrial transcription machinery in mitonuclear coevolution and speciation

    Identification of disease-causing genes using microarray data mining and gene ontology

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    Background: One of the best and most accurate methods for identifying disease-causing genes is monitoring gene expression values in different samples using microarray technology. One of the shortcomings of microarray data is that they provide a small quantity of samples with respect to the number of genes. This problem reduces the classification accuracy of the methods, so gene selection is essential to improve the predictive accuracy and to identify potential marker genes for a disease. Among numerous existing methods for gene selection, support vector machine-based recursive feature elimination (SVMRFE) has become one of the leading methods, but its performance can be reduced because of the small sample size, noisy data and the fact that the method does not remove redundant genes. Methods: We propose a novel framework for gene selection which uses the advantageous features of conventional methods and addresses their weaknesses. In fact, we have combined the Fisher method and SVMRFE to utilize the advantages of a filtering method as well as an embedded method. Furthermore, we have added a redundancy reduction stage to address the weakness of the Fisher method and SVMRFE. In addition to gene expression values, the proposed method uses Gene Ontology which is a reliable source of information on genes. The use of Gene Ontology can compensate, in part, for the limitations of microarrays, such as having a small number of samples and erroneous measurement results. Results: The proposed method has been applied to colon, Diffuse Large B-Cell Lymphoma (DLBCL) and prostate cancer datasets. The empirical results show that our method has improved classification performance in terms of accuracy, sensitivity and specificity. In addition, the study of the molecular function of selected genes strengthened the hypothesis that these genes are involved in the process of cancer growth. Conclusions: The proposed method addresses the weakness of conventional methods by adding a redundancy reduction stage and utilizing Gene Ontology information. It predicts marker genes for colon, DLBCL and prostate cancer with a high accuracy. The predictions made in this study can serve as a list of candidates for subsequent wet-lab verification and might help in the search for a cure for cancers

    Anxiety and depression in patients with gastrointestinal cancer: does knowledge of cancer diagnosis matter?

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    <p>Abstract</p> <p>Background</p> <p>Gastrointestinal cancer is the first leading cause of cancer related deaths in men and the second among women in Iran. An investigation was carried out to examine anxiety and depression in this group of patients and to investigate whether the knowledge of cancer diagnosis affect their psychological distress.</p> <p>Methods</p> <p>This was a cross sectional study of anxiety and depression in patients with gastrointestinal cancer attending to the Tehran Cancer Institute. Anxiety and depression was measured using the Hospital Anxiety and Depression Scale (HADS). This is a widely used valid questionnaire to measure psychological distress in cancer patients. Demographic and clinical data also were collected to examine anxiety and depression in sub-group of patients especially in those who knew their cancer diagnosis and those who did not.</p> <p>Results</p> <p>In all 142 patients were studied. The mean age of patients was 54.1 (SD = 14.8), 56% were male, 52% did not know their cancer diagnosis, and their diagnosis was related to esophagus (29%), stomach (30%), small intestine (3%), colon (22%) and rectum (16%). The mean anxiety score was 7.6 (SD = 4.5) and for the depression this was 8.4 (SD = 3.8). Overall 47.2% and 57% of patients scored high on both anxiety and depression. There were no significant differences between gender, educational level, marital status, cancer site and anxiety and depression scores whereas those who knew their diagnosis showed a significant higher degree of psychological distress [mean (SD) anxiety score: knew diagnosis 9.1 (4.2) vs. 6.3 (4.4) did not know diagnosis, P < 0.001; mean (SD) depression score: knew diagnosis 9.1 (4.1) vs. 7.9 (3.6) did not know diagnosis, P = 0.05]. Performing logistic regression analysis while controlling for demographic and clinical variables studied the results indicated that those who knew their cancer diagnosis showed a significant higher risk of anxiety [OR: 2.7, 95% CI: 1.1–6.8] and depression [OR: 2.8, 95% CI: 1.1–7.2].</p> <p>Conclusion</p> <p>Psychological distress was higher in those who knew their cancer diagnosis. It seems that the cultural issues and the way we provide information for cancer patients play important role in their improved or decreased psychological well-being.</p

    Coping with demand volatility in retail pharmacies with the aid of big data exploration

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    Data management tools and analytics have provided managers with the opportunity to contemplate inventory performance as an ongoing activity by no longer examining only data agglomerated from ERP systems, but also, considering internet information derived from customers' online buying behaviour. The realisation of this complex relationship has increased interest in business intelligence through data and text mining of structured, semi-structured and unstructured data, commonly referred to as "big data" to uncover underlying patterns which might explain customer behaviour and improve the response to demand volatility. This paper explores how sales structured data can be used in conjunction with non-structured customer data to improve inventory management either in terms of forecasting or treating some inventory as "top-selling" based on specific customer tendency to acquire more information through the internet. A medical condition is considered - namely pain - by examining 129 weeks of sales data regarding analgesics and information seeking data by customers through Google, online newspapers and YouTube. In order to facilitate our study we consider a VARX model with non-structured data as exogenous to obtain the best estimation and we perform tests against several univariate models in terms of best fit performance and forecasting

    Non-coding regions of nuclear-DNA-encoded mitochondrial genes and intergenic sequences are targeted by autoantibodies in breast cancer

    Get PDF
    Autoantibodies against mitochondrial-derived antigens play a key role in chronic tissue inflammation in autoimmune disorders and cancers. Here, we identify autoreactive nuclear genomic DNA (nDNA)-encoded mitochondrial gene products (GAPDH, PKM2, GSTP1, SPATA5, MFF, TSPOAP1, PHB2, COA4, and HAGH) recognized by breast cancer (BC) patients’ sera as nonself, supporting a direct relationship of mitochondrial autoimmunity to breast carcinogenesis. Autoreactivity of multiple nDNA-encoded mitochondrial gene products was mapped to protein-coding regions, 3’ untranslated regions (UTRs), as well as introns. In addition, autoantibodies in BC sera targeted intergenic sequences that may be parts of long non-coding RNA (lncRNA) genes, including LINC02381 and other putative lncRNA neighbors of the protein-coding genes ERCC4, CXCL13, SOX3, PCDH1, EDDM3B, and GRB2. Increasing evidence indicates that lncRNAs play a key role in carcinogenesis. Consistent with this, our findings suggest that lncRNAs, as well as mRNAs of nDNA-encoded mitochondrial genes, mechanistically contribute to BC progression. This work supports a new paradigm of breast carcinogenesis based on a globally dysfunctional genome with altered function of multiple mitochondrial and non-mitochondrial oncogenic pathways caused by the effects of autoreactivity-induced dysregulation of multiple genes and their products. This autoimmunity-based model of carcinogenesis will open novel avenues for BC treatment
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