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Navarro C.L.,French Institute of Health and Medical Research | Navarro C.L.,Aix - Marseille University | Esteves-Vieira V.,Laboratory of Molecular Genetics | Courrier S.,French Institute of Health and Medical Research | And 31 more authors.
European Journal of Human Genetics

Restrictive dermopathy (RD) is a rare and extremely severe congenital genodermatosis, characterized by a tight rigid skin with erosions at flexure sites, multiple joint contractures, low bone density and pulmonary insufficiency generally leading to death in the perinatal period. RD is caused in most patients by compound heterozygous or homozygous ZMPSTE24 null mutations. This gene encodes a metalloprotease specifically involved in lamin A post-translational processing. Here, we report a total of 16 families for whom diagnosis and molecular defects were clearly established. Among them, we report seven new ZMPSTE24 mutations, identified in classical RD or Mandibulo-acral dysplasia (MAD) affected patients. We also report nine families with one or two affected children carrying the common, homozygous thymine insertion in exon 9 and demonstrate the lack of a founder effect. In addition, we describe several new ZMPSTE24 variants identified in unaffected controls or in patients affected with non-classical progeroid syndromes. In addition, this mutation update includes a comprehensive search of the literature on previously described ZMPSTE24 mutations and associated phenotypes. Our comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele. © 2014 Macmillan Publishers Limited All rights reserved. Source

Jardim G.A.M.,Federal University of Minas Gerais | Reis W.J.,Federal University of Minas Gerais | Ribeiro M.F.,Federal University of Minas Gerais | Ottoni F.M.,Federal University of Minas Gerais | And 8 more authors.
RSC Advances

In our continued search for novel trypanocidal compounds, arylamine, chalcone, triazolic, triazole-carbohydrate and chalcogenium derivatives containing a naphthoquinone scaffold were prepared; in addition to electrochemical studies, these compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Among the thirty-eight compounds herein evaluated, six were found to be more potent against trypomastigotes than the standard drug benznidazole, with IC50/24 h values between 52.9 and 89.5 μM. © The Royal Society of Chemistry 2015. Source

Ceccaldi R.,French Institute of Health and Medical Research | Ceccaldi R.,Hematology Laboratory Assistance Publique Hopitaux Of Paris Aphp | Ceccaldi R.,University Paris Diderot | Briot D.,French Institute of Health and Medical Research | And 24 more authors.
Journal of Clinical Investigation

DNA damage checkpoints in the cell cycle may be important barriers against cancer progression in human cells. Fanconi anemia (FA) is an inherited DNA instability disorder that is associated with bone marrow failure and a strong predisposition to cancer. Although FA cells experience constitutive chromosomal breaks, cell cycle arrest at the G2 DNA damage checkpoint, and an excess of cell death, some patients do become clinically stable, and the mechanisms underlying this, other than spontaneous reversion of the disease-causing mutation, are not well understood. Here we have defined a clonal phenotype, termed attenuation, in which FA patients acquire an abrogation of the G2 checkpoint arrest. Attenuated cells expressed lower levels of CHK1 (also known as CHEK1) and p53. The attenuation could be recapitulated by modulating the ATR/CHK1 pathway, and CHK1 inhibition protected FA cells from cell death. FA patients who expressed the attenuated phenotype had mild bone marrow deficiency and reached adulthood, but several of them eventually developed myelodysplasia or leukemia. Better understanding of attenuation might help predict a patient's clinical course and guide choice of treatment. Our results also highlight the importance of evaluating the cellular DNA damage checkpoint and repair pathways in cancer therapies in general. Source

Frangione V.,University of Insubria | Mortara L.,University of Insubria | Castellani P.,Laboratory of Cellular Biology | De Lerma Barbaro A.,University of Insubria | Accolla R.S.,University of Insubria
International Journal of Cancer

In our study, we have investigated whether tumors of distinct histological origin can be rejected if expressing CIITA-driven MHC class II molecules. Moreover, we assessed whether antitumor lymphocytes generated by this approach could be used as an immunotherapeutic tool for established cancers. Stable CIITA-transfectants of C51colon adenocarcinoma, RENCA renal adenocarcinoma, WEHI-164 sarcoma as well as TS/A mammary adenocarcinoma were generated. Tumor cells transfectants were injected in vivo, and their growth kinetics and recipient's immune response were analyzed. Tumor rejection and/or retardation of growth was found for the first 3 CIITA-transfected tumor cell lines and confirmed for TS/A-CIITA. Animals rejecting CIITA-transfected tumors acquired specific immunological memory as demonstrated by resistance to challenge with parental tumors. Adoptive cell transfer experiments demonstrated that tumor immunity correlates with the efficient priming of CD4+ T helper cells and the consequent activation of CD8+ T lymphocytes. T cells from TS/A-vaccinated mice were used in an adoptive immunotherapy model of established tumors. The results showed the cure at early stages and significantly prolonged survival at later stages of tumor progression. Importantly, CD4+ T cells were clearly superior to CD8+ T cells in antitumor protective function. Interestingly, the protective phenotype was associated to both a Th1 and Th2 polarization of the immune effectors. These results establish the general application of our tumor vaccine model and disclose the additional application of this strategy for producing better lymphocyte effectors for adoptive antitumor immunotherapy. © 2010 UICC. Source

Micol J.B.,University Paris Diderot | Raffoux E.,University Paris Diderot | Boissel N.,University Paris Diderot | Lengline E.,University Paris Diderot | And 10 more authors.
European Journal of Cancer

Purpose Acute promyelocytic leukaemia (APL) therapy with all-trans retinoic acid and chemotherapy is associated with a high cure rate in clinical trials. As some patients are not enrolled in these trials due to early severe events, these results might be overestimated. To address this issue, we reviewed all APL patients referred to the Hospital Saint-Louis within the 2000-2010 period, with a special focus on inclusion in recruiting trials. Patients and methods One hundred patients (including eight children) with newly diagnosed APL were admitted during this period, which covered two consecutive APL trials conducted by the French-Belgian-Swiss APL group. Results The rate of patients not enrolled within recruiting trials was 29%. The main reason for non-inclusion was protocol ineligibility related to disease severity at diagnosis. Non-enrolled patients more frequently had white blood cell count (WBC) ≥ 50 × 109/L (31% versus 8%; p =.01), platelet count < 40 × 10 9/L (97% versus 65%; p =.001) and microgranular variant APL (38% versus 11%; p =.004) and were more frequently admitted in intensive care unit during induction (41% versus 24%; p =.094). Early mortality rate was higher in non-enrolled patients (21% versus 3%; p =.007), translating into a lower complete remission rate (79% versus 96%; p =.007) and lower event-free survival (65% versus 84% at 5 years; p =.05), while disease-free survival was similar in both non-enrolled and enrolled patient groups (81% versus 88% at 5 years; p =.68). Conclusion Initial APL severity leads to a significant proportion of patients non-registered within clinical trials, which may underestimate the real early mortality, which remained nonetheless less than 10% in this study. © 2014 Elsevier Ltd. All rights reserved. Source

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