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Brunetto De Farias C.,University Hospital Research Center | Brunetto De Farias C.,University of Porto | Heinen T.E.,University Hospital Research Center | Koehler-Santos P.,University Hospital Research Center | And 17 more authors.
Oncology | Year: 2010

Objective: Neurotrophin and neuropeptide pathways are emerging targets in cancer. Here we show that brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are present in colorectal cancer and that BDNF levels are increased in tumors compared to nontumor tissue. In addition, we investigate the role of BDNF in influencing the response of colorectal cancer cells to inhibition of gastrin-releasing peptide receptors (GRPR). Methods: Fresh-frozen sporadic colorectal adenocarcinoma specimens and adjacent nonneoplastic tissue from 30 patients, as well as paraffin-embedded colorectal cancer samples from 21 patients, were used in this study. Cell proliferation and mRNA and protein levels were examined in HT-29 or SW620 cells treated with a GRPR antagonist, human recombinant BDNF (hrBDNF), a Trk antagonist K252a, or cetuximab. Results: Expression of BDNF and TrkB was detected in tumor samples and cell lines. BDNF levels were higher in tumor samples compared to nonneoplastic tissue. BDNF expression and secretion were increased by GRPR blockade in HT-29 cells through a mechanism dependent on epidermal growth factor receptors. Treatment with hrBDNF prevented the effect of GRPR blockade on cell proliferation, whereas a Trk inhibitor reduced proliferation. Conclusions: BDNF and TrkB are present in colorectal cancer and might contribute to resistance to GRPR antagonists. Copyright © 2011 S. Karger AG, Basel.

Jobim M.R.,Hospital Of Clinicas Of Porto Alegre | Jobim M.,Hospital Of Clinicas Of Porto Alegre | Salim P.H.,Hospital Of Clinicas Of Porto Alegre | Portela P.,Hospital Of Clinicas Of Porto Alegre | And 12 more authors.
Human Immunology | Year: 2013

Breast cancer is the main cause of cancer-related death among women, with a 0.5% increase in incidence per year. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study was to evaluate the association between the KIR genes and HLA alleles in patients with breast cancer and healthy controls. Two hundred thirty patients with breast cancer and 272 healthy controls were typed for HLA class I and KIR genes by PCR-SSO. When both groups were compared, the presence of inhibitory KIR2DL2 receptors was significantly higher in breast cancer patients than in healthy controls. No significant differences were found for HLA-C2 and HLA-Bw4. However, a higher frequency of HLA-C1 in breast cancer patients was observed. These findings suggest a potential role for the KIR gene system in breast cancer. Further studies to confirm this observation are warranted. © 2013 American Society for Histocompatibility and Immunogenetics.

News Article | October 26, 2016
Site: www.eurekalert.org

MONTREAL, Oct. 20, 2016 - A Canada-US study led by Luis Barreiro, a professor at the University of Montreal's Department of Pediatrics and researcher at the Sainte-Justine University Hospital Center, has demonstrated that Americans of African descent have a stronger immune response to infection compared to Americans of European descent. The study establishes for the first time this difference in immune responses and shows that it is mostly genetic -- inherited from our ancestors and influenced by a relatively recent natural selection. The study is published today in the scientific journal Cell. The study was conducted among 175 Americans, half of which were of African descent, the other half being of European descent, in collaboration with the University of California, Wayne State University, Cornell University, the University of Minnesota, and Duke University. While the immune system of African Americans responds more strongly, Professor Barreiro is careful to qualify it as better: "The immune system of African Americans responds differently, but we cannot conclude that it is better, since a stronger immune response also has negative effects, including greater susceptibility to autoimmune inflammatory diseases such as Crohn's disease. Too much inflammation can damage organs and leave sequelae. In short, a strong immune response can be beneficial in some areas but a disadvantage in others. The immune system reacts to infection by causing inflammation (redness, heat, swelling, etc.) to neutralize and eliminate the infection. It was already known to scientists that African Americans are more susceptible to autoimmune inflammatory diseases and thus more likely to suffer from tuberculosis or scleroderma, for example. The 175 participants in Professor Barreiro's study provided blood samples, from which were extracted macrophages ¬-- cells of the immune system whose role is to kill pathogens responsible for infection. The research team then infected the macrophages with two kinds of bacteria (Listeria and Salmonella) to observe various immune responses: after 24 hours of infection, the macrophages from African Americans killed the bacteria three times faster. The research team also uncovered the molecular mechanisms acting on the genes responsible for these differences in immune responses. "This is one of the firsts of our study," said Barreiro. People of African and European descent have intermingled over the past centuries, and we are even able to determine which part of an individual's immune system is associated with African ancestry and which part with European ancestry." "Although we found these differences in immune responses between African and European Americans, we are still unable to demonstrate what evolutionary pressures led to the observed differences. One of our hypotheses is that in the prehistoric period, after human populations had migrated out of Africa, they were exposed to fewer pathogens (bacteria, viruses, parasites), which reduced the immune response and thus tissue inflammation. This reduction in the immune response (and inflammation) was most likely an advantage because of the adverse consequences of acute or chronic inflammation, which are major contributors to the development of autoimmune inflammatory diseases." Another hypothesis is that the weaker immune response detected in Europeans is the result of a less vigorous natural selection in an environment in which there were fewer, or at least different, pathogens compared to Africa. Neanderthals also played a role in the immune response to infection. Neanderthals, before disappearing, colonized Europe, but not Africa. In the process, they mixed their genes with African Cro-Magnons, who were spread throughout Europe. The analysis of Barreiro's team shows that about 3% of the genes involved in the differences in immune responses between African and European Americans come from Neanderthals! "There is still much to do. For example, we have not yet studied the immune response to viruses and parasites. In addition, genetics explains only about 30% of the observed differences in immune responses. Our future studies should focus on other factors, emphasizing the influence of the environment and our behaviour. The idea is to find immune mechanisms to help understand why some individuals react differently from others in the presence of certain viruses and bacteria," said Barreiro. Luis Barreiro specializes in the evolution of immune responses and was named one of the "40 under 40" (most promising researchers) published in 2014 by the prestigious journal Cell. The first time he set foot in a laboratory after completing his graduate studies in biotechnology at the University of Lisbon in his native Portugal, he found his vocation. After graduating, he obtained a six-month internship in mycobacterial genetics at the Pasteur Institute in Paris. Within five years he had completed a doctorate in human population genetics. After receiving his Ph.D., Barreiro moved to the United States, where he did a postdoctoral fellowship in functional genomics at the University of Chicago's Department of Human Genetics. Today, the same theme runs through Luis Barreiro's work at the University of Montreal and the Sainte-Justine University Hospital Research Center, which he joined in 2011. He is the holder of the Canadian Research Chair in Functional and Evolutionary Genomics of the Immune System. The main project of his laboratory is to discover and define the genetic bases of the variations underlying the differences in immune responses between individuals and human populations. While Barreiro's team is among the two or three groups in the world interested in immune responses and their genetic basis, it is the only one to explore this issue among different species of primates. http://www. Y. Nedelec, J. Sanz, G. Baharian, Z. A. Szpiech, A. Pacis, A. Dumaine, J.-C. Grenier, A. Freiman, A. J. Sams, S. Hebert, A. Pagé Sabourin, F. Luca, R. Blekhman, R. D. Hernandez, R. Pique-Regi, J. Tung, V. Yotova et L. B. Barreiro published the article "Genetic ancestry and natural selection drive population differences in immune responses to pathogens in human" in the journal Cell on October 2016. This study was funded by the Canadian Institutes of Health Research (Grants 301538 and 232519), the Human Frontiers Science Program (CDA-00025/2012), and the Canada Research Chairs Program (950-228993). Y.N. received a grant from the Network of Applied Genetic Medicine Network (RMGA); A.P.S. received a grant from the Fonds de recherche du Québec-Nature et technologies (FRQNT); and G.B. received a grant from the Fonds de recherche du Québec-Santé (FRQS).

News Article | November 28, 2016
Site: www.eurekalert.org

Social status is one of the most important factors in predicting the risk of disease and mortality in humans and other social mammals. A new study by the University of Montreal, Duke University (USA), and Emory University (USA) published in Science reveals that low social status alone can alter immune regulation, even in the absence of variation in access to resources, health care, and at-risk behaviours for health. "In short, two individuals with access to the same dietary resources and the same health care and exhibiting the same behaviours have different immune responses to infection depending on whether they have a high or low social status," said Luis Barreiro, Professor in the Department of pediatrics at the University of Montreal's Faculty of Medicine and researcher at the Sainte-Justine University Hospital Research Center. To demonstrate the biological basis of the influence of social status on the immune system, the researchers combined genomics with manipulation of the social status of 45 female macaques, a species close to humans and having a linear and stable social hierarchy. "We used macaques because it is impossible to conduct this experiment on humans for obvious ethical reasons," explained Professor Barreiro, who co-led the study with Professor Jenny Tung. "For the moment, we have only used females, but we hope to reproduce the study with males in the near future." The researchers formed nine groups of females who lived together for one year. They then formed new groups to upset the dominance ranks among the females and study the effect of the changes on their immune systems. The researchers ensured that all the animals had access to as much food as needed, and veterinarians regularly checked that they were not sick or injured, to control for these variables. In analyzing the results, the researchers discovered that the cells of macaques with low social status had a stronger pro-inflammatory response to infection compared to the cells of individuals with high social status. A pro-inflammatory response occurs when the immune system causes inflammation (e.g., redness, heat, swelling) to neutralize and eliminate bacterial or viral infections. Strong tissue or organ inflammation can save the life of the infected individual; however, disproportionate inflammation can damage the organs and leave after-affects. This may partly explain why people with low social status have a higher risk of developing cardiovascular and inflammatory diseases. For their part, macaques with high social status showed a stronger antiviral immune response compared to those with low social status. In addition, the researchers observed that these differences in immune responses were reversible. Indeed, when a low social status macaque achieved high social status, its immune system adopted the immune response associated with high social status. What to do with the results? Should this discovery encourage our societies to level out differences in social status as much as possible? Professor Barreiro does not believe so: "The history of mankind has shown us that there will always be inequalities in human society. In my opinion, the thing to do is to understand as best as possible how our immune system works and what fringes of the population are more at risk of suffering from a certain disease, and to find solutions in this regard," he concluded. N. Snyder-Mackler, J. Sanz, J. N. Kohn, J. F. Brinkworth, S. Morrow, A.O. Shaver, J.-C. Grenier, R. Pique-Regi, Z. P. Johnson, M. E. Wilson, L. B. Barreiro, and J. Tung, "Social status alters immune regulation and response to infection in macaques", Science, November 25, 2016. The study was supported by grants from the National Institutes of Health (USA), the National Science Foundation (USA), the Canada Research Chairs Program, the Natural Sciences and Engineering Research Council of Canada, and the Fonds de recherche du Québec.

Sarra-Bournet C.,University Hospital Research Center | Sarra-Bournet C.,Laval University | Sarra-Bournet C.,National Polytechnic Institute of Toulouse | Sarra-Bournet C.,CNRS LAPLACE Lab | And 8 more authors.
Advanced Materials Research | Year: 2010

Functionalized plasma polymer thin films were obtained in a dielectric barrier discharge at atmospheric pressure in an atmosphere of N2 and C2H4. The coatings were hydrophilic, adherent, chemically stable and presented a surface concentration of NH2 suitable for further biomolecule conjugation. Covalent grafting of a linking arm (glutaric anhydride) and subsequent conjugation of fibronectin, a protein of the extracellular matrix, were successful. Finally, endothelial cell adhesion experiments were performed directly on the functionalized thin films as well as on the conjugated coatings. Effects on cell adhesion were observed as a function of the plasma thin film deposition parameters. © (2010) Trans Tech Publications.

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