Late orogenic carboniferous extensions in the Variscan French Massif Central

International audienceThe Variscan French Massif Central experienced two successive stages of extension from Middle Carboniferous to Early Permian. In the northern Massif Central, the first stage began in the late Visean, immediately after nappe stacking, and is well recorded by Namurian-Westphalian synkinematic plutonism. The Middle Carboniferous leucogranites widespread in the NW Massif Central (Limousin and Sioule area) were emplaced within a crust extending along a NE-SW direction. At the same time, the hanging wall or "Guéret extensional allochton" moved toward the SE. Several examples of the synextensional plutonism are also recognized in central Limousin: Saint Mathieu dome, La Porcherie, and Cornil leucogranites. These examples illustrate the relationship between granite emplacement and crustal scale deformation characterized by NW-SE stretching and NE-SW shortening. In the central and southern Massif Central (Cévennes, Châtaigneraie, and Margeride areas), plutonism is dominantly granodioritic and exhibits the same structural features: NW-SE maximum stretching and overturning to the SE. Middle Carboniferous (Namurian-Westphalian) extension was parallel to the Variscan belt both in the Massif Central and southern Armorican area. This extensional regime was active from the late Visean in the north, while compression dominated in the southernmost domains (Montagne Noire and Pyrenées). The second extensional stage occurred from Late Carboniferous to Early Permian. This event was responsible for the opening of intramontane coal basins, brittle deformation in the upper crust, and ductile normal faulting localized on the margin of cordierite granite-migmatite domes. Data from the coal basins show that the half-graben is the dominant structural style, except for basins located along submeridianal left-lateral faults which have pull-apart geometries. Late Carboniferous extension occurred along the NE-SW direction. The NE-SW maximum stretching direction can be found in the whole Massif Central but is more developed in the eastern part. The extensional direction is transverse to the general trend of the belt, and top-to-the-NE shearing is dominant. Correlations of these two extension directions with neighboring Variscan massifs are discussed

Hommage à Madame Grévy : deux amours sublimes ! inspiré par deux anges !, ma mère ! et la patrie ! / poésie de Labernardière (Claude)

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Abstract 2143: Mechanistic study of the relative cytotoxicity of doxorubicin loaded nanoparticle formulation compared to free doxorubicin in hepatocellular carcinoma (HCC) cell lines

Abstract Background and Aims Efficacy of doxorubicin encapsulated into a biodegradable network (NP) is currently studied in phase III compared to Best Standard of Care in patients with advanced HCC (Relive study). Preclinical studies demonstrated that NP allowed the reversion of chemo-resistance and enhanced cytotoxicity compared to free doxorubicin on resistant human hepatoma and mestastatic liver cells. In this study the mechanism of action of NP in overcoming HCC cellular resistance as well as the mechanisms of cellular uptake were investigated in representative cell lines. Methods Determination of IC20 of NP in the presence of influx drug inhibitors targeting endocytosis (clathrin or caveolae-dependent; sucrose and Genistein respectively), phagocytosis (LY-294002) or macropinocytosis (Cytochalasin D) were performed on two HCC cell lines (HuH7 and HepG2) using a proliferation assay. Each uptake inhibitor was added 30 min before incubation with NP on cultured cells for measurement of proliferation followed by cellular quantification of free doxorubicin by HPLC. The same assays were also performed using Verapamil as an inhibitor of the major multidrug resistance protein P-glycoprotein (P-gp). The P-gp ATPase activity in plasma membrane preparations from vehicle, doxorubicin and NP-treated cells was determined using the Pgp-Glo assay system. Results NP showed lower IC20 than free doxorubicin in HCC proliferation assays. None of the influx inhibitors used in combination with NP impaired the inhibitory effect of NP on the rate of proliferation of HCC cell lines. Similarly, Verapamil did not modulate the cellular potency of NP on the rate of proliferation in these cell lines. Doxorubicin quantification in cellular extracts and supernatant of NP-treated cells confirmed these results. Furthermore, NP had no effect on P-gp ATPase activity in isolated plasma membrane samples. Conclusions All these results demonstrated that NP did not enter into the HCC cell via an active transport mechanism, but by passive diffusion as occurs with free Doxorubicin. The absence of inhibition of the P-gp ATPase by NP implies that the Doxorubicin-nanoparticle conjugate (ion pair) probably ‘hinders’ the doxorubicin from being a substrate for the pump rather than by a direct interaction. The implication of these data on the role of NP in the treatment of HCC will be discussed. Citation Format: Véronique Trochon-joseph, Caroline Lemarchand, Vincent Hayes, Yamina Rayah, Jean-Louis Labernardière, Graham Dixon. Mechanistic study of the relative cytotoxicity of doxorubicin loaded nanoparticle formulation compared to free doxorubicin in hepatocellular carcinoma (HCC) cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2143.</jats:p

Human Immunodeficiency Virus Type 1 Variants Isolated from Single Plasma Samples Display a Wide Spectrum of Neutralization Sensitivity

Individuals infected with human immunodeficiency virus type 1 (HIV-1) harbor a mixture of viral variants with different sequences and in some instances with different phenotypic properties. Major and rapid fluctuations in the proportion of viral variants coexisting in an infected individual can be observed under strong pharmacological and immune selective pressure. Because of the short half-life of HIV-infected cells and of HIV virions in the blood, plasma virus populations are highly relevant to HIV evolution in the face of these selective pressures. Here we analyzed the sensitivity to antibody-mediated neutralization of viral variants coexisting in the plasma virus populations of two infected patients. For each patient, several replication-competent viral clones were constructed that carry primary envelope gene sequences obtained from a single plasma sample. Viral clones differed in their tropism and replicative capacity and in the number and positions of glycosylation sites in the envelope glycoproteins. Viruses were tested against heterologous and autologous sera obtained at different time points. Interestingly, we found that viral variants coexisting in each plasma sample were highly heterogeneous in terms of sensitivity to neutralization. The order of sensitivity depended on the serum used and was not associated with virus tropism. The neutralization potency of sera increased with the duration of the infection for both autologous and heterologous neutralization

Abstract 3076: A novel nanoparticle formulation of doxorubicin is clearly differentiated from free doxorubicin in overcoming resistance mechanisms in chemo-resistant tumors

Abstract Background and Aims. Chemo-resistance in hepatocellular carcinoma (HCC) tumor cells can be mediated by several mechanisms including P-gp efflux pumps and drug sequestration by the autophagy process. This study investigates the potential of doxorubicin loaded nanoparticle (NP) to reverse chemo-resistance by these mechanisms compared to free doxorubicin. We present the preclinical evaluation of anti-tumor effects of NP as monotherapy and in combination with standard agents used in treatment of HCC, pancreatic and sarcoma cancers. A phase III clinical study comparing NP to Best Standard of Care (Relive study) in patients with advanced HCC is in the final stages of recruitment with preliminary results expected in 2H 2017. Methods. Tumor cell lines were incubated with drugs in cell proliferation assay. In vivo efficacy of NP alone (4-8 mg/kg) or in combination with current and investigational treatments for pancreatic cancer (e.g. Gemcitabine, Erlotinib, Abraxane) and HCC (Sorafenib, Regorafenib and Lenvatinib) were performed in mouse tumor models using tumor weight as primary endpoint. In all experiments NP was compared to administration of free doxorubicin. Doxorubicin quantification in tumor and organs to asses PK and biodistribution was also performed using an LC/MS based method. Autophagy was measured by cell proliferation in the presence of inhibitors e.g.. Concanamycin A, Hydroxychloroquine sulfate added 30 min before incubation with the test compound. Results. NP showed a dose-dependent inhibition of cell proliferation in all resistant cancer cell lines tested with a superior activity compared to free doxorubicin and other tested drugs. In contrast to free doxorubicin, NP showed consistent anti-proliferative activity in the absence/presence of inhibitors of P-gp pumps and autophagy. In a range of in vivo models, NP was preferentially taken up by the tumor tissue and significantly reduced tumor growth when compared with free doxorubicin and with at least equivalent reduction in tumor growth compared to current treatments. Furthermore NP administered in combination with current treatments significantly increased the inhibitory effect of each drug without additional toxicity (as measured by no change in body weight). The results comparing efficacy of NP alone and in combination in HCC, pancreatic and sarcoma cancer models will be presented. Conclusions. These results demonstrate that NP is clearly differentiated from free doxorubicin, in 1) overcoming resistance mechanisms linked to efflux and autophagy, and 2) having a superior biodistribution profile both of which results in significantly enhanced activity on chemo-resistant tumors. NP also provides an opportunity to combine with other agents, enhancing activity without increasing toxicity. The implications of these results on the further development of NP will be discussed. Citation Format: Véronique Trochon-joseph, Christelle Zandanel, Caroline Lemarchand, Vincent Hayes, Séverine Rochas, Yamina Rayah, Jean-Louis Labernardière, Graham Dixon, Francoise Bono. A novel nanoparticle formulation of doxorubicin is clearly differentiated from free doxorubicin in overcoming resistance mechanisms in chemo-resistant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3076. doi:10.1158/1538-7445.AM2017-3076</jats:p

The V Protein of Tioman Virus Is Incapable of Blocking Type I Interferon Signaling in Human Cells

The capacity of a virus to cross species barriers is determined by the development of bona fide interactions with cellular components of new hosts, and in particular its ability to block IFN-α/β antiviral signaling. Tioman virus (TioV), a close relative of mumps virus (MuV), has been isolated in giant fruit bats in Southeast Asia. Nipah and Hendra viruses, which are present in the same bat colonies, are highly pathogenic in human. [...] Because STAT2 binding was previously identified as a host restriction factor for some Paramyxoviridae, we established STAT2 sequence from giant fruit bats, and binding to TioV-V was tested. Surprisingly, TioV-V interaction with STAT2 from giant fruit bats is also extremely weak and barely detectable. Altogether, our observations question the capacity of TioV to appropriately control IFN-α/β signaling in both human and giant fruit bats that are considered as its natural host