Genotoxicity and Gene Expression in the Rat Lung Tissue following Instillation and Inhalation of Different Variants of Amorphous Silica Nanomaterials (aSiO2 NM)

This article belongs to the Special Issue Cytotoxicity and Genotoxicity of Nanomaterials.Several reports on amorphous silica nanomaterial (aSiO2 NM) toxicity have been questioning their safety. Herein, we investigated the in vivo pulmonary toxicity of four variants of aSiO2 NM: SiO2_15_Unmod, SiO2_15_Amino, SiO2_7 and SiO2_40. We focused on alterations in lung DNA and protein integrity, and gene expression following single intratracheal instillation in rats. Additionally, a short-term inhalation study (STIS) was carried out for SiO2_7, using TiO2_NM105 as a benchmark NM. In the instillation study, a significant but slight increase in oxidative DNA damage in rats exposed to the highest instilled dose (0.36 mg/rat) of SiO2_15_Amino was observed in the recovery (R) group. Exposure to SiO2_7 or SiO2_40 markedly increased oxidative DNA lesions in rat lung cells of the exposure (E) group at every tested dose. This damage seems to be repaired, since no changes compared to controls were observed in the R groups. In STIS, a significant increase in DNA strand breaks of the lung cells exposed to 0.5 mg/m3 of SiO2_7 or 50 mg/m3 of TiO2_NM105 was observed in both groups. The detected gene expression changes suggest that oxidative stress and/or inflammation pathways are likely implicated in the induction of (oxidative) DNA damage. Overall, all tested aSiO2 NM were not associated with marked in vivo toxicity following instillation or STIS. The genotoxicity findings for SiO2_7 from instillation and STIS are concordant; however, changes in STIS animals were more permanent/difficult to revert.This work was funded by the Portuguese Foundation for Science and Technology (FCT) through ERA-NET SIINN project NanoToxClass (SIINN/0001/2013). FB and MJB are recipients of FCT PhD scholarships (SFRH/BD/101060/2014 and SFRH/BD/12046/2016). Thanks are due to FCT/MCTES for the financial support through national funds to EPIUnit (UIDB/04750/2020). J. Laloy performed STIS at the University of Namur with funding provided by BfR (grant agreement number 1329-561). F. Debacq-Chainiaux is a research associate at FRS-FNRS (National Funds for Scientific Research, Belgium).info:eu-repo/semantics/publishedVersio

Thérapie épigénétique des cancers du poumon: Effet anti-tumoral du valproate sur le cancer bronchique à petites cellules

Lung cancer is the leading cause of cancer-related death worldwide. Among lung carcinomas, the outcome of small cell lung carcinoma (SCLC) patients is the poorest of any histological subtype with five-year survival rate of less than 20 and 5 % for limited and extensive stage respectively. Based on increasing evidence that inhibitors of histones deacetylases (HDAC) have anticancer properties, the goal of this study was to evaluate the ability of valproate (VPA) to improve efficacy of chemotherapeutic regimen in SCLC. We show that VPA directly induces apoptosis of SCLC cell lines at concentrations relevant for clinical uses. Furthermore, VPA synergizes with two chemotherapeutic regimen used in first (cisplatin + etoposide) and second line (cyclophosphamid + vindesine + doxorubicin) treatments. Both mitochondrial and death receptor pathways are involved in VPA-induced apoptosis. Although VPA promotes production of reactive oxygen species, free radical scavenger N-acetylcystein is not sufficient to inhibit apoptosis. As expected, VPA triggers hyperacetylation of histone H3 and increases expression of p21. VPA reduces levels of BclxL, induces cleavage of Bid, translocation of Bax to mitochondria, release of cytochrome c into cytosol and phosphorylation of Erk and H2AX. Transcriptomic analyses by microarrays and quantitative RT-PCR have underscored a series of genes candidates potentially implicated into sensitivity of SCLC to VPA. Among these, the Fzd7 receptor of the WNT pathway is essential for VPA proapoptotic activity. Efficiency of VPA combined to first and second line chemotherapeutic agents is supported by preclinical models of SCLC cells engrafted into SCID mice. The second line combination is presently tested in a clinical trial with patients presenting with refractory or relapsing small cell lung cancer (protocol 01081 at http://www.elcwp.org)

Sous le masque de Pythagore: À propos du livre 15 des "Métamorphoses"

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Les deux Turnus

La pagination indiquée dans la zone "Pages" est celle du tiré à part, numérisé par les Bibliothèques de l'ULB. La pagination, telle qu'elle apparait dans la revue est pp. 157-212.info:eu-repo/semantics/publishe

Le Pô et le Matinus

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Microlight Aircraft for Radiometric Surveying Applied to Land Resources Assessment and Monitoring in Mali (West Africa)

A MICROLIGHT AIRCRAFT HAS BEEN USED TO OBTAIN AND RECORD CONCURRENT, NEAR CONTINUOUS, SPECTRAL RESPONSES IN MSS AND SPOT BANDS OVER VARIOUS GROUND FEATURES: WATER BODIES, GEOMORPHOLOGICAL FEATURES, AQUATIC VEGETATION AND STUBBLES. THE EXPERIMENT WAS PERFORMED IN MALI, ALONG THE NIGER RIVER, DURING NOVEMBER 1985. THE AIRBORNE INSTRUMENTATION, DEVELOPED AS A PROTOTYPE FOR THIS EXPERIMENT, ALSO INCLUDED FLYING HEIGHT MEASUREMENTS BY A LASER RANGE-FINDER AND A COLOUR VIDEO-CAMERA. SPECTRAL DATA AND FLYING HEIGHT (5 TO 80 METERS) WERE SCANNED EVERY 0.1 SEC. AND RECORDED ON THE AUDIO CHANNEL OF A VIDEOTAPE, AFTER MULTIPLEXING AND ANALOGUE TO DIGITAL CONVERSION (8 CHANNELS). CONCLUSION: - THE MEASURING AND RECORDING SYSTEM, ALTHOUGH LIGHT AND SIMPLE, PROVED TO BE VERY EFFICIENT FOR AUTOMATIC SURVEY IN A TROPICAL ENVIRONMENT. - SPECTRAL REFLECTANCE PROFILES ARE FESSIBLE IN A VERY SHORT TIME (SOME MINU- TES) OVER A WIDE RANGE OF OBJECTS, ALLOWING HOMOGENEOUS INCOMING LIGHT CONDI- TIONS. - HEIGHT MEASUREMENTS CAN PROVIDE VERY USEFULL INFORMATION FOR THE GEOMETRIC DESCRIPTION OF THE VEGETATION COVER. - MICROLIGHT AIRCRAFT IS PROVING TO BE HIGHLY SUITABLE AS A PLATFORM FOR LOW- COST AERIAL SURVEY, COMPLEMENTARY TO CONVENTIONAL METHODS. - LARGE SCALE AERIAL PHOTOGRAPHY IS ONE OF THE POTENTIALITIES OF MICROLIGHT AIRCRAFT: AN EXPERIMENTAL CAMPAGN ACCORDING TO AFRICAN ENVIRONMENT, IS PLANNED FOR SEPTEMBER/OCTOBER 1986 IN MALINA-NOT AVAILABL

Unique Pattern of Component Gene Disruption in the NRF2 Inhibitor KEAP1/CUL3/RBX1 E3-Ubiquitin Ligase Complex in Serous Ovarian Cancer

The NFE2-related factor 2 (NRF2) pathway is critical to initiate responses to oxidative stress; however, constitutive activation occurs in different cancer types, including serous ovarian carcinomas (OVCA). The KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex is a regulator of NRF2 levels. Hence, we investigated the DNA-level mechanisms affecting these genes in OVCA. DNA copy-number loss (CNL), promoter hypermethylation, mRNA expression, and sequence mutation for KEAP1, CUL3, and RBX1 were assessed in a cohort of 568 OVCA from The Cancer Genome Atlas. Almost 90% of cases exhibited loss-of-function alterations in any components of the NRF2 inhibitory complex. CNL is the most prominent mechanism of component disruption, with RBX1 being the most frequently disrupted component. These alterations were associated with reduced mRNA expression of complex components, and NRF2 target gene expression was positively enriched in 90% of samples harboring altered complex components. Disruption occurs through a unique DNA-level alteration pattern in OVCA. We conclude that a remarkably high frequency of DNA and mRNA alterations affects components of the KEAP1/CUL3/RBX1 complex, through a unique pattern of genetic mechanisms. Together, these results suggest a key role for the KEAP1/CUL3/RBX1 complex and NRF2 pathway deregulation in OVCA