Toxicology Studies on Lewisite and Sulfur Mustard Agents: Genetic Toxicity of Sulfur Mustard (HD) in Chinese Hamster Ovary Cells Final Report

The cytotoxic, clastogenic and mutagenic effects of sulfur nustard in Chinese hamster ovary cells are described in this reoort. The cytotoxicity data indicate that micromolar amounts of HC are highly toxic in microrolar amounts. Chromosone aberration frequencies increased in a dose-dependent manner over a dose range of 0. 5 to 1.0 {micro}m and SCE increased in a dose-dependent fashion in the dose range of 0.0625 to 0.25 {micro}M. Mutation induction at the HGPRT locus was sporadic, but the majority of the exoosures resulted in mutation frequencies which were 1.2 to 4.3 fold higher than the spontaneous frequencies

Toxicology Studies on Lewisite and Sulfur Mustard Agents: Genetic Toxicity of Sulfur Mustard (HD) in Chinese Hamster Ovary Cells Final Report

The cytotoxic, clastogenic and mutagenic effects of sulfur nustard in Chinese hamster ovary cells are described in this reoort. The cytotoxicity data indicate that micromolar amounts of HC are highly toxic in microrolar amounts. Chromosone aberration frequencies increased in a dose-dependent manner over a dose range of 0. 5 to 1.0 {micro}m and SCE increased in a dose-dependent fashion in the dose range of 0.0625 to 0.25 {micro}M. Mutation induction at the HGPRT locus was sporadic, but the majority of the exoosures resulted in mutation frequencies which were 1.2 to 4.3 fold higher than the spontaneous frequencies

Toxicology Studies of Lewisite and Sulfur Mustard Agents: Genetic Toxicity of Lewisite (L) In Chinese Hamster Ovary Cells

The cytotoxic clastogenic and mutagenic effects of the arsenic containing vesicant, Lewisite (L) [dichloro(2-chlorovinyl) arsine], have been investigated using Chinese hamster ovary cells. One hour exposures to Lewisite were cytotoxic in uM amounts. The cell survival response yields a D37 of 0.6 uM and an extrapolation number of 2.5. The mutagenic response at the hypoxantnine-guanine phosporibosyl transferase (HGPRT) locus was sporadic and not significantly greater than control values when cells were exposed over a range of 0.125 to2.0 uM. Sister chromatid exchange (SCE) induction, a measure of chromosomal rearrangement, was weakly positive over a range of 0.25 to 1.0 uM but the values were not significantly greater than the control response. Chromosomal aberrations were induced at 0.75 and 1.0 UMin one experiment and 0.5 and 0.75 uM in another experiment. The Induced values were significantly greater than the control values. Lewisite appears to be cytotoxic and clastogenic in our investigations but SCE and mutation at the HGPRT locus are not significantly greater than control values. Lewisita toxicity was in some ways similar to radiomimetic chemicals such as bleomycin

Suppression of BCL6 Function by HDAC Inhibitor Mediated Acetylation and Chromatin Modification Enhances BET Inhibitor Effects in B-cell Lymphoma Cells

Multiple genetic aberrations in the regulation of BCL6, including in acetyltransferase genes, occur in clinically aggressive B-cell lymphomas and lead to higher expression levels and activity of this transcriptional repressor. BCL6 is, therefore, an attractive target for therapy in aggressive lymphomas. In this study romidepsin, a potent histone deacetylase inhibitor (HDACi), induced apoptosis and cell cycle arrest in Burkitt and diffuse large B-cell lymphoma cell lines, which are model cells for studying the mechanism of action of BCL6. Romidepsin caused BCL6 acetylation at early timepoints inhibiting its function, while at later timepoints BCL6 expression was reduced and target gene expression increased due to chromatin modification. MYC contributes to poor prognosis in aggressive lymphoma. MYC function is reduced by inhibition of chromatin readers of the bromodomain and extra-terminal repeat (BET) family, which includes BRD4. The novel combination of romidepsin and JQ1, a BRD4 inhibitor was investigated and showed synergy. Collectively we suggest that the combination of HDACi and BRD4i should be pursued in further pre-clinical testing.Funding: The work was supported by grants SAF2014-53526-R and SAF2017-88026-R from MINECO, Spanish Government, to M.D.D. and J.L. (partially funded by FEDER program from European Union). M.G.C. was recipient of a “Marcos Fernández” fellowship from Leukemia and Lymphoma foundation. L.G.G. was recipient of a FPI fellowship from Spanish Government

Cell-type-specific control elements of the lymphotropic papovavirus enhancer.

Lymphotropic papovavirus (LPV) exhibits a highly restricted host range, in which only cells of primate B-lymphocyte origin are permissive for infection. Its enhancer element contributes to this tropism, since transcriptional potentiation is confined to cells of the hematopoietic lineage. Nuclear extracts from B and T cells, but not from HeLa cells, contain protein factors that interact specifically with the LPV 63-base-pair enhancer repeat, as demonstrated by DNase I footprinting and gel retardation experiments. Within the repeat three sequence motifs were identified: the core motif, the Pu box, and a novel element named T motif. Functional analysis demonstrated that these motifs as well as some sequences upstream of the repeat contribute to the optimal activity of the enhancer. There are clear differences between the patterns of binding of the B and T lymphocyte nuclear proteins to the enhancer which are also reflected in the transcriptional activity of the enhancer in both cell types. Furthermore, the activity of the LPV enhancer and its interaction with nuclear proteins seem to be regulated during B-cell differentiation

PAX - A MURINE MULTIGENE FAMILY OF PAIRED BOX-CONTAINING GENES

A murine multigene family has been identified that shares a conserved sequence motif, the paired box, with developmental control and tissue-specific genes of Drosophila. To date five murine paired box-containing genes (Pax genes) have been described and one, Pax-1, has been associated with the developmental mutant phenotype undulated. Here we describe the paired boxes of three novel Pax genes, Pax-4, Pax-5, and Pax-6. Comparison of the eight murine paired domains of the mouse, the five Drosophila paired domains, and the three human paired domains shows that they fall into six distinct classes: class I comprises Pox meso, Pax-1, and HuP48; class II paired, gooseberry-proximal, gooseberry-distal, Pax-3, Pax-7, HuP1, and HuP2; class III Pax-2, Pax-5, and Pax-8; class IV Pax-4; class V Pox neuro; and class VI Pax-6. Pax-1 and the human gene HuP48 have identical paired domains, as do Pax-3 and HuP2 as well as Pax-7 and HuP1, and are likely to represent homologous genes in mouse and man. Identical intron-exon structure and extensive sequence homology of their paired boxes suggest that several Pax genes represent paralogs. The chromosomal location of all novel Pax genes and of Pax-3 and Pax-7 has been determined and reveals that they are not clustered

ON THE ROLE OF THE HETERO METAL ATOM IN THE N2-REDUCING PROTEIN OF NITROGENASE

Müller A, Jostes R, Krickemeyer E, Bögge H. ON THE ROLE OF THE HETERO METAL ATOM IN THE N2-REDUCING PROTEIN OF NITROGENASE. NATURWISSENSCHAFTEN. 1987;74(8):388-389