Derivation of occupational exposure limits: Differences in methods and protection levels.

Frameworks for deriving occupational exposure limits (OELs) and OEL-analogue values (such as derived-no-effect levels [DNELs]) in various regulatory areas in the EU and at national level in Germany were analysed. Reasons for differences between frameworks and possible means of improving transparency and harmonisation were identified. Differences between assessment factors used for deriving exposure limits proved to be one important reason for diverging numerical values.

Distributions for time, interspecies and intraspecies extrapolation for deriving occupational exposure limits.

This work aimed at improving the empirical database of time (i.e., exposure duration), interspecies and intraspecies extrapolation when deriving occupational exposure limits (OELs).

Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma.

CARM1 is an arginine methyltransferase with diverse histone and non-histone substrates implicated in the regulation of cellular processes including transcriptional co-activation and RNA processing. CARM1 overexpression has been reported in multiple cancer types and has been shown to modulate oncogenic pathways in in vitro studies. Detailed understanding of the mechanism of action of CARM1 in oncogenesis has been limited by a lack of selective tool compounds, particularly for in vivo studies.

A687V EZH2 is a driver of histone H3 lysine 27 (H3K27) hypertrimethylation.

The EZH2 methyltransferase silences gene expression through methylation of histone H3 on lysine 27 (H3K27). Recently, EZH2 mutations have been reported at Y641, A677, and A687 in non-Hodgkin lymphoma. Although the Y641F/N/S/H/C and A677G mutations exhibit clearly increased activity with substrates dimethylated at lysine 27 (H3K27me2), the A687V mutant has been shown to prefer a monomethylated lysine 27 (H3K27me1) with little gain of activity toward H3K27me2.

Long residence time inhibition of EZH2 in activated polycomb repressive complex 2.

EZH2/PRC2 catalyzes transcriptionally repressive methylation at lysine 27 of histone H3 and has been associated with numerous cancer types. Point mutations in EZH2 at Tyr641 and Ala677 identified in non-Hodgkin lymphomas alter substrate specificity and result in increased trimethylation at histone H3K27. Interestingly, EZH2/PRC2 is activated by binding H3K27me3 marks on histones, and this activation is proposed as a mechanism for self-propagation of gene silencing.

EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation.

The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B cells and targeted by somatic mutations in B cell lymphomas. Here, we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B cell differentiation.

Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2.

The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. As part of a drug discovery program targeting EZH2, we have identified highly potent, selective, SAM-competitive, and cell-active EZH2 inhibitors, including GSK926 (3) and GSK343 (6). These compounds are small molecule chemical tools that would be useful to further explore the biology of EZH2.

EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.

In eukaryotes, post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumour types.

Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27).

Trimethylation of histone H3 on lysine 27 (H3K27me3) is a repressive posttranslational modification mediated by the histone methyltransferase EZH2. EZH2 is a component of the polycomb repressive complex 2 and is overexpressed in many cancers. In B-cell lymphomas, its substrate preference is frequently altered through somatic mutation of the EZH2 Y641 residue.

JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia.

There is increasing evidence that tumor-associated macrophages promote the malignancy of some cancers. Colony-stimulating factor-1 (CSF-1) is expressed by many tumors and is a growth factor for macrophages and mediates osteoclast differentiation. Herein, we report the efficacy of a novel orally active CSF-1 receptor (CSF-1R) kinase inhibitor, JNJ-28312141, in proof of concept studies of solid tumor growth and tumor-induced bone erosion.

Reassessment of occupational exposure limits.

Background: Although the Netherlands currently has its own procedure for evaluating chemical compounds and setting occupational exposure limits (OELs), most of these limits were originally adopted in the 1970s from threshold limit values (TLVs) set by the American Conference of Governmental Industrial Hygienists (ACGIH). However, beginning in the late 1980s, criticism about non-scientific considerations being used to set TLV's suggested that TLVs might not offer sufficient health protection to workers. This situation prompted the Dutch Ministry of Social Affairs and Employment to request that the Health Council of the Netherlands reassess the health protection of MAC values that were contained in the 1994 Dutch MAC list.

4-Amino-6-piperazin-1-yl-pyrimidine-5-carbaldehyde oximes as potent FLT-3 inhibitors.

A series of 4-amino-6-piperazin-1-yl-pyrimidine-5-carbaldehyde oximes has been discovered and developed as potent FLT3 tyrosine kinase inhibitors. The series exhibited potent antiproliferative activity against both an FLT3 ITD-mutated human leukemic cell line as well as a wild-type FLT3 BaF(3) expressed cell line. The structure-activity relationship of this class of compounds is described.

Identification of 2-acylaminothiophene-3-carboxamides as potent inhibitors of FLT3.

A series of 2-acylaminothiophene-3-carboxamides has been identified which exhibit potent inhibitory activity against the FLT3 tyrosine kinase. Compound 44 inhibits the isolated enzyme (IC50 = 0.027 microM) and blocks the proliferation of MV4-11 cells (IC50 = 0.

2-Hydroxy-4,6-diamino-[1,3,5]triazines: a novel class of VEGF-R2 (KDR) tyrosine kinase inhibitors.

2-Hydroxy-4,6-diamino-[1,3,5]triazines are described which are a novel class of potent inhibitors of the VEGF-R2 (flk-1/KDR) tyrosine kinase. 4-(Benzothiazol-6-ylamino)-6-(benzyl-isopropyl-amino)-[1,3,5]triazin-2-ol (14d) exhibited low nanomolar potency in the in vitro enzyme inhibition assay (IC(50) = 18 nM) and submicromolar inhibitory activity in a KDR-induced MAP kinase autophosphorylation assay in HUVEC cells (IC(50) = 280 nM), and also demonstrated good in vitro selectivity against a panel of growth factor receptor tyrosine kinases. Further, 14d showed antiangiogenic activity in an aortic ring explant assay by blocking endothelial outgrowths in rat aortas with an IC(50) of 1 microM.

Effects of di-n-butylamine on the respiratory system of Wistar (WU) rats after subchronic inhalation.

Aim of the study was to investigate the potential toxic effects of di-n-butylamine (DBA), a known skin and eye irritating compound, on the respiratory tract after inhalation exposure for up to 91 days in male and female rats [Crl:(WI)WU BR]. To check whether and to what degree the no-observed-(adverse)-effect level (NO(A)EL) decreases with increasing study duration, serial sacrifices were performed after 3 and 28 days, respectively. Based on two dose range-finding studies, the concentrations for this study were determined with 0 (clean air), 50, 150, and 450 mg/m(3).