ABSTRACT
BACKGROUND: Although some studies show that there could be a genetic predisposition to develop Multiple Sclerosis (MS), attempts to find genetic signatures related to MS diagnosis and development are extremely rare. METHOD: We carried out a retrospective analysis of two different microarray datasets, using machine learning techniques to understand the defective pathways involved in this disease. We have modeled two data sets that are publicly accessible. The first was used to establish the list of most discriminatory genes; whereas, the second one was utilized for validation purposes. RESULTS: The analysis provided a list of high discriminatory genes with predictive cross-validation accuracy higher than 95%, both in learning and in blind validation. The results were confirmed via the holdout sampler. The most discriminatory genes were related to the production of Hemoglobin. The biological processes involved were related to T-cell Receptor Signaling and co-stimulation, Interferon-Gamma Signaling and Antigen Processing and Presentation. Drug repositioning via CMAP methodologies highlighted the importance of Trichostatin A and other HDAC inhibitors. CONCLUSIONS: The defective pathways suggest viral or bacterial infections as plausible mechanisms involved in MS development. The pathway analysis also confirmed coincidences with Epstein-Barr virus, Influenza A, Toxoplasmosis, Tuberculosis and Staphylococcus Aureus infections. Th17 Cell differentiation, and CD28 co-stimulation seemed to be crucial in the development of this disease. Furthermore, the additional knowledge provided by this analysis helps to identify new therapeutic targets.
Subject(s)
Databases, Nucleic Acid , Drug Repositioning , Machine Learning , Metabolic Networks and Pathways , Models, Immunological , Multiple Sclerosis , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Humans , Male , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/immunology , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Oligonucleotide Array Sequence Analysis , Retrospective Studies , Signal Transduction/drug effects , Signal Transduction/immunologyABSTRACT
The present study was undertaken to explore the possible mechanisms of the behavioral alterations that develop in response to cancer and to cancer therapy. For this purpose we used a syngeneic heterotopic mouse model of human papilloma virus (HPV)-related head and neck cancer in which cancer therapy is curative. Mice implanted or not with HPV+ tumor cells were exposed to sham treatment or a regimen of cisplatin and radiotherapy (chemoradiation). Sickness was measured by body weight loss and reduced food intake. Motivation was measured by burrowing, a highly prevalent species specific behavior. Tumor-bearing mice showed a gradual decrease in burrowing over time and increased brain and liver inflammatory cytokine mRNA expression by 28 days post tumor implantation. Chemoradiation administered to healthy mice resulted in a mild decrease in burrowing, body weight, and food intake. Chemoradiation in tumor-bearing mice decreased tumor growth and abrogated liver and brain inflammation, but failed to attenuate burrowing deficits. PCR array analysis of selected hypoxia and mitochondrial genes revealed that both the tumor and chemoradiation altered the expression of genes involved in mitochondrial energy metabolism within the liver and brain and increased expression of genes related to HIF-1α signaling within the brain. The most prominent changes in brain mitochondrial genes were noted in tumor-bearing mice treated with chemoradiation. These findings indicate that targeting mitochondrial dysfunction following cancer and cancer therapy may be a strategy for prevention of cancer-related symptoms.
Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Genes, Mitochondrial , Head and Neck Neoplasms/therapy , Illness Behavior/drug effects , Illness Behavior/radiation effects , Animals , Brain/drug effects , Brain/immunology , Brain/pathology , Brain/radiation effects , Chemoradiotherapy , Cytokines/metabolism , Gene Expression/drug effects , Gene Expression/radiation effects , Genes, Mitochondrial/drug effects , Genes, Mitochondrial/radiation effects , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/physiopathology , Illness Behavior/physiology , Liver/drug effects , Liver/immunology , Liver/pathology , Liver/radiation effects , Male , Mice, Inbred C57BL , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/radiation effects , Motivation/drug effects , Motivation/physiology , Motivation/radiation effects , Motor Activity/drug effects , Motor Activity/physiology , Motor Activity/radiation effects , Neoplasm Transplantation , Oropharyngeal Neoplasms/genetics , Oropharyngeal Neoplasms/pathology , Oropharyngeal Neoplasms/physiopathology , Oropharyngeal Neoplasms/therapy , Papillomaviridae , Radiation-Sensitizing Agents/pharmacologyABSTRACT
PURPOSE. Post-traumatic stress disorder (PTSD) is associated with inflammatory-related medical conditions. This review examines studies of immune function in individuals with PTSD to determine if excessive inflammation is associated with PTSD. CONCLUSIONS. Current studies suggest an excess of inflammatory actions of the immune system in individuals with chronic PTSD. High levels of inflammatory cytokines have also been linked to PTSD vulnerability in traumatized individuals. There is also evidence that excessive inflammation is in part due to insufficient regulation by cortisol. PRACTICE IMPLICATIONS. An excess of inflammatory immune activity may contribute to health declines in individuals with PTSD, and treating PTSD symptoms may reduce these risks.
