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Kayadjanian N.,Transbiomed | Burghes A.,Ohio State University | Finkel R.S.,Nemours Childrens Hospital | Mercuri E.,Catholic University | And 3 more authors.
Orphanet Journal of Rare Diseases | Year: 2013

Spinal muscular atrophy (SMA) is the most common lethal recessive disease in childhood, and there is currently no effective treatment to halt disease progression. The translation of scientific advances into effective therapies is hampered by major roadblocks in clinical trials, including the complex regulatory environment in Europe, variations in standards of care, patient ascertainment and enrolment, a narrow therapeutic window and a lack of biomarkers of efficacy. In this context, SMA-Europe organized its first international workshop in July 2012 in Rome, gathering 34 scientists, clinicians and representatives of patient organizations to establish recommendations for improving clinical trials for SMAa. © 2013 Kayadjanian et al.; licensee BioMed Central Ltd.

Benleulmi M.S.,Transbiomed | Matysiak J.,Transbiomed | Henriquez D.R.,University of Chile | Vaillant C.,CNRS Physics Laboratory | And 12 more authors.
Retrovirology | Year: 2015

Background: Retroviral integration depends on the interaction between intasomes, host chromatin and cellular targeting cofactors as LEDGF/p75 or BET proteins. Previous studies indicated that the retroviral integrase, by itself, may play a role in the local integration site selection within nucleosomal target DNA. We focused our study on this local association by analyzing the intrinsic properties of various retroviral intasomes to functionally accommodate different chromatin structures in the lack of other cofactors. Results: Using in vitro conditions allowing the efficient catalysis of full site integration without these cofactors, we show that distinct retroviral integrases are not equally affected by chromatin compactness. Indeed, while PFV and MLV integration reactions are favored into dense and stable nucleosomes, HIV-1 and ASV concerted integration reactions are preferred into poorly dense chromatin regions of our nucleosomal acceptor templates. Predicted nucleosome occupancy around integration sites identified in infected cells suggests the presence of a nucleosome at the MLV and HIV-1 integration sites surrounded by differently dense chromatin. Further analyses of the relationships between the in vitro integration site selectivity and the structure of the inserted DNA indicate that structural constraints within intasomes could account for their ability to accommodate nucleosomal DNA and could dictate their capability to bind nucleosomes functionally in these specific chromatin contexts. Conclusions: Thus, both intasome architecture and compactness of the chromatin surrounding the targeted nucleosome appear important determinants of the retroviral integration site selectivity. This supports a mechanism involving a global targeting of the intasomes toward suitable chromatin regions followed by a local integration site selection modulated by the intrinsic structural constraints of the intasomes governing the target DNA bending and dictating their sensitivity toward suitable specific nucleosomal structures and density. © Benleulmi et al.

PubMed | Bordeaux University Hospital Center, French Institute of Health and Medical Research, Transbiomed and Roger Williams University
Type: Journal Article | Journal: The American journal of pathology | Year: 2016

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of diseases primarily involving the skin that could have an aggressive course with circulating blood cells, especially in Szary syndrome and transformed mycosis fungoides. So far, few CTCL cell lines have been adapted for invivo experiments and their tumorigenicity has not been adequately assessed, hampering the use of a reproducible model for CTCL biological evaluation. In fact, both patient-derived xenografts and cell line xenografts at subcutaneous sites failed to provide a robust tool, because engraftment was dependent on mice strain and cell line subtype. Herein, we describe an original method of intrahepatic injection into adult NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ mice liver of both aggressive (My-La, HUT78, HH, MAC2A, and MAC2B) and indolent (FE-PD and MAC1) CTCL cell lines. Six of the seven CTCL cell lines were grafted with a high rate of success (80%). Moreover, this model provided a quick (15 days) and robust assay for invivo evaluation of CTCL cell lines tumorigenicity and therapeutic response in preclinical studies. Such a reproducible model can be therefore used for further functional studies and invivo drug testing.

PubMed | University of Bordeaux 1, University of Chicago, University of Lausanne, French National Center for Scientific Research and 5 more.
Type: Journal Article | Journal: Chemistry & biology | Year: 2015

The cellular DNA repair hRAD51 protein has been shown to restrict HIV-1 integration both invitro and invivo. To investigate its regulatory functions, we performed a pharmacological analysis of the retroviral integration modulation by hRAD51. We found that, invitro, chemical activation of hRAD51 stimulates its integration inhibitory properties, whereas inhibition of hRAD51 decreases the integration restriction, indicating that the modulation of HIV-1 integration depends on the hRAD51 recombinase activity. Cellular analyses demonstrated that cells exhibiting high hRAD51 levels prior to de novo infection are more resistant to integration. On the other hand, when hRAD51 was activated during integration, cells were more permissive. Altogether, these data establish the functional link between hRAD51 activity and HIV-1 integration. Our results highlight the multiple and opposite effects of the recombinase during integration and provide new insights into the cellular regulation of HIV-1 replication.

Cosnefroy O.,University of Bordeaux Segalen | Cosnefroy O.,UK National Institute for Medical Research | Cosnefroy O.,Transbiomed | Jaspart A.,University of Bordeaux Segalen | And 15 more authors.
Cellular and Molecular Life Sciences | Year: 2013

Higher eukaryotic organisms have a variety of specific and nonspecific defense mechanisms against viral invaders. In animal cells, viral replication may be limited through the decrease in translation. Some viruses, however, have evolved mechanisms that counteract the response of the host. We report that infection by HIV-1 triggers acute decrease in translation. The human protein kinase GCN2 (eIF2AK4) is activated by phosphorylation upon HIV-1 infection in the hours following infection. Thus, infection by HIV-1 constitutes a stress that leads to the activation of GCN2 with a resulting decrease in protein synthesis. We have shown that GCN2 interacts with HIV-1 integrase (IN). Transfection of IN in amino acid-starved cells, where GCN2 is activated, increases the protein synthesis level. These results point to an as yet unknown role of GCN2 as an early mediator in the cellular response to HIV-1 infection, and suggest that the virus is able to overcome the involvement of GCN2 in the cellular response by eliciting methods to maintain protein synthesis. © 2013 Springer Basel.

Metifiot M.,Transbiomed | Amrane S.,University of Bordeaux Segalen | Mergny J.-L.,University of Bordeaux Segalen | Andreola M.-L.,Transbiomed
Biochimie | Year: 2015

During clinical trials, a number of fully characterized molecules are dropped along the way because they do not provide enough benefit for the patient. Some of them show limited side effects and might be of great use for other applications. AS1411 is a nucleolin-targeting aptamer that underwent phase II clinical trials as anticancer agent. Here, we show that AS1411 exhibits extremely potent antiviral activity and is therefore an attractive new lead as anti-HIV agent. © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Bellecave P.,Bordeaux University Hospital Center | Bellecave P.,University of Bordeaux Segalen | Bellecave P.,Transbiomed | Malato L.,Bordeaux University Hospital Center | And 12 more authors.
International Journal of Antimicrobial Agents | Year: 2014

The antiviral efficacy of raltegravir (RAL) has been proven against human immunodeficiency virus type 1 (HIV-1) subtypes B and C but remained to be determined against other subtypes. Therefore, the enzymatic activities as well as RAL resistance of HIV-1 subtype A and CRF01-AE integrases (INs) were investigated. Previously published subtype A and CRF01-AE IN sequences from RAL-naïve patients were aligned to generate consensus sequences for both IN subtypes. Subtype A and CRF01-AE INs encoded by these consensus sequences as well as the corresponding enzymes harbouring the N155H resistance mutation were expressed and purified. Enzymatic activities of subtype A and CRF01-AE INs were analysed with regard to typical 3′-end processing (3′-P) and strand transfer (ST) activities both in the presence and absence of RAL and were compared with subtype B IN as well as with the corresponding INs harbouring the N155H resistance mutation. Subtypes B, A and CRF01-AE INs showed similar 3′-P and ST activities. In the presence of RAL, the three wild-type INs exhibited ST activity IC50 values (50% inhibitory concentrations) of 86.3 ± 32.5, 158.3 ± 99.0 and 100.0 ± 65.7 nM, respectively. Analysis of 3′-P activity in the presence of RAL revealed IC50 > 10 μM for all three enzymes. The three INs harbouring the N155H mutation presented in vitro low but similar resistance levels to RAL. In conclusion, INs from HIV-1 subtypes B, A and CRF01-AE showed similar responses to RAL in vitro, suggesting the potency of this antiretroviral drug to treat HIV-1 subtype A- and CRF01-AE-infected patients. © 2014 Elsevier B.V. and the International Society of Chemotherapy.

PubMed | University of Bordeaux Segalen and Transbiomed
Type: | Journal: Biochimie | Year: 2015

During clinical trials, a number of fully characterized molecules are dropped along the way because they do not provide enough benefit for the patient. Some of them show limited side effects and might be of great use for other applications. AS1411 is a nucleolin-targeting aptamer that underwent phase II clinical trials as anticancer agent. Here, we show that AS1411 exhibits extremely potent antiviral activity and is therefore an attractive new lead as anti-HIV agent.

Ricard A.S.,French Institute of Health and Medical Research | Pain C.,French Institute of Health and Medical Research | Daubos A.,French Institute of Health and Medical Research | Ezzedine K.,University Hospitals | And 5 more authors.
Experimental Dermatology | Year: 2012

We have hypothesised that melanocytes disappear in vitiligo because they are weakly attached to the epidermal basal membrane (melanocytorrhagy). In the epidermis, attachment of melanocytes to collagen IV is mediated through DDR1, which is under the control of CCN3. DDR1 genetic variants have been associated with vitiligo in patients of different ethnic origin. In vitro studies have shown that inhibition of CCN3 induces the detachment of melanocytes. We have studied in parallel the expression of CCN3 and DDR1 in lesional and perilesional skin of patients with vitiligo and the impact of the silencing of CCN3 and DDR1 in normal human melanocytes on their behaviour in epidermal reconstructs. Our in vivo study provides evidence of a dysregulation of the DDR1-CCN3 interaction in vitiligo skin as melanocytes remaining in perilesional skin did not express CCN3. Expression of DDR1 was decreased in lesional versus perilesional vitiligo skin in the majority of patients, and the expression of collagen IV was found decreased in all patients. Silencing of CCN3 in melanocytes induced a significant inhibition of cell adhesion to collagen IV whereas melanocytes transduced with shDDR1 still adhered well on collagen IV and did not increase melanocyte loss in epidermal reconstructs as compared with normal melanocytes. Melanocyte detachment was observed but not in all reconstructs using CCN3 silenced melanocytes. Overall, our study confirms that a downregulation of CCN3 is implicated in melanocyte adhesion in part through DDR1. In vitiligo skin, the interaction of CCN3 with other molecules, such as TGFβ and CCN2, needs to be addressed. © 2012 John Wiley & Sons A/S.

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