BCL2L10 is a predictive factor for resistance to Azacitidine in MDS and AML patients

Azacitidine is the leading compound to treat patients suffering myelodysplastic syndrome (MDS) or AML with less than 30% of blasts, but a majority of patients is primary refractory or rapidly relapses under treatment. These patients have a drastically reduced life expectancy as compared to sensitive patients. Therefore identifying predictive factors for AZA resistance is of great interest to propose alternative therapeutic strategies for non-responsive patients. We generated AZA-resistant myeloid cell line (SKM1-R) that exhibited increased expression of BCL2L10 an anti-apoptotic Bcl-2 family member. Importantly, BCL2L10 knockdown sensitized SKM1-R cells to AZA effect suggesting that increased BCL2L10 expression is linked to AZA resistance in SKM1-R. We next established in 77 MDS patients that resistance to AZA is significantly correlated with the percentage of MDS or AML cells expressing BCL2L10. In addition, we showed that the proportion of BCL2L10 positive bone marrow cells can predict overall survival in MDS or AML patients. We propose a convenient assay in which the percentage of BCL2L10 expressing cells as assessed by flow cytometry is predictive of whether or not a patient will become resistant to AZA. Therefore, systematic determination of BCL2L10 expression could be of great interest in newly diagnosed and AZA-treated MDS patients

Escherichia coli α-Hemolysin Counteracts the Anti-Virulence Innate Immune Response Triggered by the Rho GTPase Activating Toxin CNF1 during Bacteremia

International audienceThe detection of the activities of pathogen-encoded virulence factors by the innate immune system has emerged as a new paradigm of pathogen recognition. Much remains to be determined with regard to the molecular and cellular components contributing to this defense mechanism in mammals and importance during infection. Here, we reveal the central role of the IL-1 beta signaling axis and Gr1+ cells in controlling the Escherichia coli burden in the blood in response to the sensing of the Rho GTPase-activating toxin CNF1. Consistently, this innate immune response is abrogated in caspase-1/11-impaired mice or following the treatment of infected mice with an IL-1 beta antagonist. In vitro experiments further revealed the synergistic effects of CNF1 and LPS in promoting the maturation/secretion of IL-1 beta and establishing the roles of Rac, ASC and caspase-1 in this pathway. Furthermore, we found that the Phi-hemolysin toxin inhibits IL-1 beta secretion without affecting the recruitment of Gr1+ cells. Here, we report the first example of anti-virulence-triggered immunity counteracted by a pore-forming toxin during bacteremia

Intérêt d'une approche de modélisation pour prédire la qualité des produits carnés transformés - Exemple des produits salés.

The results of the literature on the evolution of food quality are very difficult to use. Existing data are often contradictory, and always difficult to transpose from one case to another due to the difference in the type of equipment and in the processing conditions. Combined transfer to reaction modelling is appropriate to respond to this situation. This paper illustrates how the transfer-reaction modelling was applied to predict the final quality of two products:cooked meat and dry-cured ham. The approach developed in this paper can be generalized to other foods and other processes to identify what are the best scenarios to obtain a targeted quality for different food materials and types of industrial equipment

All tyrosine kinase inhibitor-resistant chronic myelogenous cells are highly sensitive to Ponatinib.

International audienceThe advent of tyrosine kinase inhibitor (TKI) therapy has considerably improved the survival of patients suffering chronic myelogenous leukemia (CML). Indeed, inhibition of BCR-ABL by imatinib, dasatinib or nilotinib triggers durable responses in most patients suffering from this disease. Moreover, resistance to imatinib due to kinase domain mutations can be generally circumvented using dasatinib or nilotinib, but the multi-resistant T315I mutation that is insensitive to these TKIs, remains to date a major clinical problem. In this line, ponatinib (AP24534) has emerged as a promising therapeutic option in patients with all kinds of BCR-ABL mutations, especially the T315I one. However and surprisingly, the effect of ponatinib has not been extensively studied on imatinib-resistant CML cell lines. Therefore, in the present study, we used several CML cell lines with different mechanisms of resistance to TKI to evaluate the effect of ponatinib on cell viability, apoptosis and signaling. Our results show that ponatinib is highly effective on both sensitive and resistant CML cell lines, whatever the mode of resistance and also on BaF3 murine B cells carrying native BCR-ABL or T315I mutation. We conclude that ponatinib could be effectively used for all types of TKI-resistant patients

Effet des paramètres d'ambiance dans les locaux d'affinage sur la qualité des fromages en conditions expérimentales au laboratoire et en locaux pilotes

Effet des paramètres d'ambiance dans les locaux d'affinage sur la qualité des fromages en conditions expérimentales au laboratoire et en locaux pilote

L'affinage des fromages fermiers lactiques

L'affinage des fromages fermiers lactique

Qualité des fromages fermiers lactiques : locaux et maitrise de l’affinage (LACTAFF)

Le programme LACTAFF (2012 – 2015) a eu pour objectif d’améliorer la maîtrise de l’affinage des fromages fermiers lactiques, technologie la plus couramment utilisée à la ferme, en fournissant des outils et des références aux producteurs et aux techniciens qui les accompagnent. Des enquêtes menées dans 49 fermes des 6 principales régions produisant ce type de fromage ont permis de caractériser la grande diversité des fromages fabriqués, des locaux, des équipements et des pratiques et d’établir des liens entre les grandes catégories de fromages et les pratiques, locaux et conditions d’ambiance. Par ailleurs, au laboratoire et en fromageries expérimentales, le rôle clé de l’hygrométrie a été quantifié en affinage, ainsi qu’au séchage où la vitesse d’air joue un rôle encore plus important. Les effets des paramètres d’ambiance sur la composition physico-chimique et les caractéristiques sensorielles des fromages ont été quantifiés pour un type de fromage donné.The « LACTAFF » program (2012-2015) aimed at improving the control of goat lactic farmhouse cheese ripening, a technology frequently used by farmers, by producing tools and references for producers and the technicians guiding them. Surveys conducted in 49 farms in the 6 main regions producing this kind of cheeses allowed to characterize the great diversity of cheeses, premises, equipment and practices, and to link cheese categories with practices, premises characteristics and air production conditions. In laboratory and experimental dairies, the key role of humidity was quantified during ripening and during drying, in which air speed is even more important. Atmospheric parameters effects on cheeses physicochemical composition and sensory characteristics were quantified for one type of cheeses. Specialist experience of cheese technology, premises design and climate control equipment and technician experience were capitalized at the same time. This project led to the writing of technical documents available online and a book about lactic farmhouse cheeses ripening

CNF1 potentiates LPS-triggered immune responses.

<p>(A) Monocytes (5x10⁵ cells per condition) isolated from mouse blood were treated with PBS (control) or with 1 μg/ml CNF1 toxin for 10 h with or without 100 ng/ml LPS. Cell culture supernatants were analyzed using mouse ELISArray kits (n = 3). The data are shown as fold inductions compared with the control condition. (B, C and D) Monocytes (5x10⁵ cells per condition) purified from mouse blood were treated for 10 h. Cells were treated as indicated with 0.1, 1, or 10 μg/ml of CNF1 toxin or the CNF1 mutant C866S alone or in combination with ultrapure <i>E</i>. <i>coli</i> LPS at 1, 10 or 100 ng/ml (n = 3). (B) KC, (C) IL-6, and (D) IL-1β cytokine secretion was analyzed using ELISA (n = 4). (E) Female BALB/c mice were intravenously infected with 10⁷ CFUs of <i>E</i>. <i>coli</i> expressing CNF1 (<i>E</i>. <i>coli</i>^CNF1+) + PBS as a control or with an <i>E</i>. <i>coli</i>^CNF1+ + IL-1β antagonist (Kineret; 1.5 mg/kg) prior to the collection of peripheral blood at 3, 6, 24 and 48 h for the measurement of bacteremia (n = 10). P-values <0.05 (*); and P-values <0.01 (**) were considered statistically significant.</p