Hofman P.,Institute for Research on Cancer and Aging |
Hofman P.,University of Nice Sophia Antipolis |
Hofman P.,Pasteur Hospital |
Hofman P.,Center Antoine Lacassagne |
And 29 more authors.
Cancer Research | Year: 2015
Colitis-associated cancer (CAC) is a complication of inflammatory bowel disease (IBD). Binding of extracellular ATP to the purinergic receptor P2RX7 has emerged as a critical event in controlling intestinal inflammation, acting to limit elevation of proinflammatory mast cells and cytokines and promote survival of regulatory T cells (Treg) and enteric neurons. In this study, we investigated the effect of P2RX7 blockade in an established mouse model of CAC. Using genetic and pharmacologic tools, we found unexpectedly thatwhile P2RX7mediated inflammatory responses, it also acted at an early time to suppress CAC development. P2RX7 blockade enhanced proliferation of intestinal epithelial cells and protected them from apoptosis. The proliferative effects of P2RX7 blockade were associated with an increased production of TGFβ1 that was sufficient to stimulate the proliferation of intestinal epithelial cells. Finally, P2RX7 blockade also altered immune cell infiltration and promoted Treg accumulation within lesions of the digestive system. Taken together, our findings reveal an unexpected role for P2RX7 in preventingCAC, suggesting cautions in the use of P2RX7 inhibitors to treat IBD given the possibility of increasing risks CAC as a result. © 2015 American Association for Cancer Research.
News Article | November 12, 2015
Like a jungle cat, this parasite sports a long tail. But until now, little was known about what role that tail plays in this dangerous jumping. Today, scientists report that without a tail, this parasitic gene can't jump efficiently. The findings could help lead to new strategies for inhibiting the movement of the parasite, called a LINE-1 retrotransposon. The research, published in Molecular Cell by a team from the University of Michigan Medical School and the Howard Hughes Medical Institute, answers a key question about how "jumping genes" move to new DNA locations. The parasite in question isn't a foreign beast, but rather a piece of DNA that carries its own instructions for making a piece of "rogue" genetic material and two proteins that can help it jump. "Jumping" allows this rogue copy to land anywhere in the DNA of a cell, causing a change called a mutation. Jumping LINE-1s - and other genetic parasites like it - are responsible for about one in every 250 disease producing mutations in humans. They've been blamed for causing a number of diseases, including hemophilia, Duchenne muscular dystrophy, and cancer. Copies of this parasite litter our DNA, though most of them can no longer jump and cause damage. For these reasons, scientists want to understand as much as possible about how this process works. Perhaps someday, this new understanding could help fight the effects of these jumps - or prevent the parasites from leaping in the first place. "Now, we have a mechanism to explain how sequences that comprise one-third of our genome have moved," says John Moran, Ph.D., senior author of the new paper and a longtime U-M and HHMI researcher studying jumping genes. "By understanding how LINE-1 jumps, we can understand how it contributes to disease." The gene that's responsible for LINE-1 jumping does its damage by first creating an RNA copy of itself. That RNA copy tells the cell to make two proteins that help make it possible for the LINE-1 RNA itself to jump into a new spot. Each copy of LINE-1 RNA has a long tail at its end that's made up of multiple copies of a substance called adenosine. Known as a "poly(A) tail", it's long been suspected of playing a role in LINE-1 jumping. But it was impossible to figure this role out because removing the tail also eliminates another key function it serves, in getting the RNA to the location where proteins are made. Like the Cheshire Cat of Alice in Wonderland, if the tail vanished, the rest of the "cat" would too. So, a postdoctoral fellow, Aurélien Doucet, Ph.D., now a research associate at the Institute for Research on Cancer and Aging in Nice, or CNRS, in France, collaborated with Jeremy Wilusz, Ph.D., now an assistant professor at the University of Pennsylvania Perelman School of Medicine, to figure out a way to delete the LINE-1 poly(A) tail to determine if it affected LINE-1 jumping. They succeeded in making a LINE-1 RNA, without a poly(A) tail, that got where it needed to in the cell to make proteins. The substitute tail allowed the scientists to see what happened when LINE-1 RNA could get to the protein-making spot, but without its usual appendage. Here's where it gets interesting. Without the poly(A) tail, almost no jumping happened - because the tailless LINE-1 RNA couldn't interact well with a protein called ORF2p. ORF2p is actually one of the two proteins that the LINE-1 RNA tells the cell to make. Once ORF2p binds to the RNA's tail, it sets in motion the steps needed for a jump to occur. Moran compares it to a Lego set - where one kind of tail could get unplugged and another slotted in to serve some, but not all, of the same functions. In other words, the LINE-1 parasite is especially crafty. LINE-1 also has a competitor parasite, called Alu. And when LINE-1 RNA lacked the tail and couldn't jump, Alu RNA did much better at jumping. Alu RNA also sports a poly(A) sequence at its end, which has already been shown to be vital to its ability to jump. But the Alu RNA doesn't contain the instructions for making a protein. This suggests, says Moran, that the two parasites compete to have access to ORF2p proteins. That is, Alu is a parasite of a parasite. Moran and his team continue to build on their new finding that poly(A) sequences are crucial for retrotransposition. They're studying how Alu interacts with ORF2p, and how the use of a replacement for the poly(A) tail may be helpful in other research. They're also interested in how the cell, or host, fights off jumping genes and protects DNA from damage. "Our DNA is a sea of junk copies of LINE-1 that can't jump, and a small minority of LINE-1s that can," says Moran, who is the Gilbert S. Omenn Collegiate Professor of Human Genetics in the U-M Department of Human Genetics. "We need to understand at the RNA level how these LINE-1 RNAs are chosen for jumping, and how we can stop them." Explore further: Two human proteins found to affect how 'jumping gene' gets around
Ilie M.I.,Institute for Research on Cancer and Aging |
Ilie M.I.,Pasteur Hospital |
Lassalle S.,Institute for Research on Cancer and Aging |
Lassalle S.,Pasteur Hospital |
And 26 more authors.
Thyroid | Year: 2014
Background: The aim of this study was to compare the detection of BRAF V600E by immunohistochemistry (IHC) using a mutation-specific antibody with molecular biology methods for evaluation of papillary thyroid carcinoma (PTC) patients. Patients and methods: This study concerned 198 consecutive conventional PTC patients, of which the majority were women (133/198; 67%), with a mean age of 56 years (range 19-79 years). BRAF mutation analysis was performed using DNA-based (direct sequencing, pyrosequencing, and SNaPshot) and IHC (VE1 antibody) methods. The sensitivity and specificity of IHC for BRAFV600E was compared with the molecular biology data. Results: A BRAF mutational result was obtained in 194 cases. A BRAFV600E mutation was detected in 153/194 (79%) cases of PTC when using at least one molecular method, and in 151/194 (78%) cases with IHC. No false positive results were noted using IHC to detect the BRAFV600E mutation. Besides this mutation, other rare BRAF mutations (BRAFV600K and BRAF K601E), used as negative controls, were consistently negative with IHC. The sensitivity and specificity of IHC for the detection of this mutation were 98.7% and 100% respectively. The IHC test demonstrated excellent performance at a level equivalent to two DNA-based counterparts (pyrosequencing and SNaPshot). Failure to achieve a result was more frequent with the direct sequencing method than with the three other methods. Conclusion: IHC using the VE1 antibody is a specific and sensitive method for the detection of the BRAFV600E mutation in PTC. IHC may be an alternative to molecular biology approaches for the routine detection of this mutation in PTC patients. © Mary Ann Liebert, Inc.
Peyrin-Biroulet L.,University of Lorraine |
Salleron J.,Institute Of Cancerologie Of Lorraine |
Filippi J.,Institute for Research on Cancer and Aging |
Reenaers C.,University of Liège |
And 5 more authors.
Journal of Crohn's and Colitis | Year: 2016
Background: Anti-tumour necrosis factor [TNF] therapy in combination with thiopurine is the most effective strategy for Crohn's disease, but raises safety concerns. Methods: In a retrospective multicentre study, we investigated long-term outcome of patients starting anti-TNF monotherapy for Crohn's disease and investigated whether introducing an immunomodulator in patients losing response to anti-TNF monotherapy is effective for resetting immunogenicity. Results: A total of 350 adult patients with Crohn's disease received either infliximab [n = 178, 51%] or adalimumab [n = 172, 49%] monotherapy. Mean duration of follow-up was 42 months. An immunomodulator was initiated in 53 patients [15%]. At last follow-up, 73.1% [n = 38] were in clinical remission [one patient with missing data]. Multivariate analysis identified anti-TNF type [higher need for starting immunomodulator for infliximab than for adalimumab; p = 0.0058] and first- vs second-/third-/fourth-line anti-TNF therapy [p = 0.014] as predictors of immunomodulator initiation. Among the 18 patients with available data, introduction of an immunomodulator was able to restore infliximab trough level within the therapeutic range and to induce clinical remission in 10 patients [55%]. Cumulative probability of remaining on anti-TNF therapy was 57.9% at 5 years among the 297 patients not starting an immunomodulator during follow-up. Conclusion: An immunomodulator was initiated in 15% of patients with Crohn's disease starting anti-TNF monotherapy. Independent predictors of immunomodulator initiation were infliximab use and second-/third-/fourth-line anti-TNF therapy. Resetting immunogenicity with an immunomodulator was effective in half of patients in a sub-study. Persistence of anti-TNF treatment at 5 years was observed in half of the 297 patients not starting an immumodulator in a real-life setting. © 2016 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved.
PubMed | University of Lorraine, Institute Of Cancerologie Of Lorraine, Jean Monnet University, University of Liège and Institute for Research on Cancer and Aging
Type: Journal Article | Journal: Journal of Crohn's & colitis | Year: 2016
Anti-tumour necrosis factor [TNF] therapy in combination with thiopurine is the most effective strategy for Crohns disease, but raises safety concerns.In a retrospective multicentre study, we investigated long-term outcome of patients starting anti-TNF monotherapy for Crohns disease and investigated whether introducing an immunomodulator in patients losing response to anti-TNF monotherapy is effective for resetting immunogenicity.A total of 350 adult patients with Crohns disease received either infliximab [n = 178, 51%] or adalimumab [n = 172, 49%] monotherapy. Mean duration of follow-up was 42 months. An immunomodulator was initiated in 53 patients [15%]. At last follow-up, 73.1% [n = 38] were in clinical remission [one patient with missing data]. Multivariate analysis identified anti-TNF type [higher need for starting immunomodulator for infliximab than for adalimumab; p = 0.0058] and first- vs second-/third-/fourth-line anti-TNF therapy [p = 0.014] as predictors of immunomodulator initiation. Among the 18 patients with available data, introduction of an immunomodulator was able to restore infliximab trough level within the therapeutic range and to induce clinical remission in 10 patients [55%]. Cumulative probability of remaining on anti-TNF therapy was 57.9% at 5 years among the 297 patients not starting an immunomodulator during follow-up.An immunomodulator was initiated in 15% of patients with Crohns disease starting anti-TNF monotherapy. Independent predictors of immunomodulator initiation were infliximab use and second-/third-/fourth-line anti-TNF therapy. Resetting immunogenicity with an immunomodulator was effective in half of patients in a sub-study. Persistence of anti-TNF treatment at 5 years was observed in half of the 297 patients not starting an immumodulator in a real-life setting.
Wimalasena T.T.,University of Nottingham |
Greetham D.,University of Nottingham |
Marvin M.E.,University of Leicester |
Liti G.,Institute for Research on Cancer and Aging |
And 8 more authors.
Microbial Cell Factories | Year: 2014
Background: During industrial fermentation of lignocellulose residues to produce bioethanol, microorganisms are exposed to a number of factors that influence productivity. These include inhibitory compounds produced by the pre-treatment processes required to release constituent carbohydrates from biomass feed-stocks and during fermentation, exposure of the organisms to stressful conditions. In addition, for lignocellulosic bioethanol production, conversion of both pentose and hexose sugars is a pre-requisite for fermentative organisms for efficient and complete conversion. All these factors are important to maximise industrial efficiency, productivity and profit margins in order to make second-generation bioethanol an economically viable alternative to fossil fuels for future transport needs.Results: The aim of the current study was to assess Saccharomyces yeasts for their capacity to tolerate osmotic, temperature and ethanol stresses and inhibitors that might typically be released during steam explosion of wheat straw. Phenotypic microarray analysis was used to measure tolerance as a function of growth and metabolic activity. Saccharomyces strains analysed in this study displayed natural variation to each stress condition common in bioethanol fermentations. In addition, many strains displayed tolerance to more than one stress, such as inhibitor tolerance combined with fermentation stresses.Conclusions: Our results suggest that this study could identify a potential candidate strain or strains for efficient second generation bioethanol production. Knowledge of the Saccharomyces spp. strains grown in these conditions will aid the development of breeding programmes in order to generate more efficient strains for industrial fermentations. © 2014 Wimalasena et al.; licensee BioMed Central Ltd.
Li J.,Nanjing University |
Li J.,Institute for Research on Cancer and Aging |
Zhou J.,Harvard University |
Wu Y.,Nanjing University |
And 3 more authors.
G3: Genes, Genomes, Genetics | Year: 2015
Amino acids typically are encoded by multiple synonymous codons that are not used with the same frequency. Codon usage bias has drawn considerable attention, and several explanations have been offered, including variation in GC-content between species. Focusing on a simple parameter-combined GC proportion of all the synonymous codons for a particular amino acid, termed GCsyn-we try to deepen our understanding of the relationship between GC-content and amino acid/codon usage in more details. We analyzed 65 widely distributed representative species and found a close association between GCsyn, GC-content, and amino acids usage. The overall usages of the four amino acids with the greatest GCsyn and the five amino acids with the lowest GCsyn both vary with the regional GC-content, whereas the usage of the remaining 11 amino acids with intermediate GCsyn is less variable. More interesting, we discovered that codon usage frequencies are nearly constant in regions with similar GC-content. We further quantified the effects of regional GC-content variation (low to high) on amino acid usage and found that GC-content determines the usage variation of amino acids, especially those with extremely high GCsyn, which accounts for 76.7% of the changed GC-content for those regions. Our results suggest that GCsyn correlates with GCcontent and has impact on codon/amino acid usage. These findings suggest a novel approach to understanding the role of codon and amino acid usage in shaping genomic architecture and evolutionary patterns of organisms. © 2015 Li et al.