Synthesis and preliminary structure-activity relationship study of 3-methylquinazolinone derivatives as EGFR inhibitors with enhanced antiproliferative activities against tumour cells.

In this paper, a set of 3-methylquniazolinone derivatives were designed, synthesised, and studied the preliminary structure-activity relationship for antiproliferative activities. All target compounds performed significantly inhibitory effects against wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and tumour cells (A431, A549, MCF-7, and NCI-H1975). In particular, compound 4d 3-fluoro-N-(4-((3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)phenyl)benzamide showed higher antiproliferative activities against all tumour cells than Gefitinib (IC50 of 3.48, 2.55, 0.87 and 6.42 µM, respectively). Furthermore, compound 4d could induce apoptosis of MCF-7 cells and arrest in G2/M phase at the tested concentration. Molecular docking and ADMET studies showed that compound 4d could closely form many hydrogen bonds with EGFRwt-TK. Therefore, compound 4d is potential to develop as novel anti-cancer drug.

Epigenomic programming in early fetal brain development.

Aim: To provide a comprehensive understanding of gene regulatory networks in the developing human brain and a foundation for interpreting pathogenic deregulation. Materials & methods: We generated reference epigenomes and transcriptomes of dissected brain regions and primary neural progenitor cells (NPCs) derived from cortical and ganglionic eminence tissues of four normal human fetuses. Results: Integration of these data across developmental stages revealed a directional increase in active regulatory states, transcription factor activities and gene transcription with developmental stage. Consistent with differences in their biology, NPCs derived from cortical and ganglionic eminence regions contained common, region specific, and gestational week specific regulatory states. Conclusion: We provide a high-resolution regulatory network for NPCs from different brain regions as a comprehensive reference for future studies.

Development, validation and application of a ventilator-associated pneumonia prevention checklist in a single cardiac surgery centre.

OBJECTIVES: The purpose of this study was to develop, validate and apply a ventilator-associated pneumonia prevention checklist in a single cardiac surgery centre. METHODS: An initial checklist was designed based on the published care bundles for prevention of ventilator-associated pneumonia; the Delphi method used for validation. A total of 20 experts were invited to score the items and give suggestions for the checklist. The final checklist was then applied to patients receiving cardiac surgery. Non-compliance with the protocol and outcome indicators were observed. RESULTS: Two rounds of Delphi were conducted. The final one-page checklist consisted of three main parts: (1) demographic data of the patient receiving cardiac surgery; (2) general assessment of the patient (3) checklist of prevention measures. The average time to complete the checklist was between two and four minutes. After the application of the checklist, the incidence of ventilator-associated pneumonia decreased from 14.48 to 5.47 episodes per thousand ventilator hours. In patients requiring >48 hours mechanical ventilation, the ventilator-associated pneumonia rate and duration of ventilation was significantly decreased. CONCLUSION: A checklist was developed for ventilator associated pneumonia based on care bundles and validated using the Delphi method. The checklist appeared to be a useful tool in preventing ventilator associated pneumonia and shortening the ventilation time.

Nucleosome Density ChIP-Seq Identifies Distinct Chromatin Modification Signatures Associated with MNase Accessibility.

Nucleosome position, density, and post-translational modification are widely accepted components of mechanisms regulating DNA transcription but still incompletely understood. We present a modified native ChIP-seq method combined with an analytical framework that allows MNase accessibility to be integrated with histone modification profiles. Application of this methodology to the primitive (CD34+) subset of normal human cord blood cells enabled genomic regions enriched in one versus two nucleosomes marked by histone 3 lysine 4 trimethylation (H3K4me3) and/or histone 3 lysine 27 trimethylation (H3K27me3) to be associated with their transcriptional and DNA methylation states. From this analysis, we defined four classes of promoter-specific profiles and demonstrated that a majority of bivalent marked promoters are heterogeneously marked at a single-cell level in this primitive cell type. Interestingly, extension of this approach to human embryonic stem cells revealed an altered relationship between chromatin modification state and nucleosome content at promoters, suggesting developmental stage-specific organization of histone methylation states.

Epigenetic and transcriptional determinants of the human breast.

While significant effort has been dedicated to the characterization of epigenetic changes associated with prenatal differentiation, relatively little is known about the epigenetic changes that accompany post-natal differentiation where fully functional differentiated cell types with limited lifespans arise. Here we sought to address this gap by generating epigenomic and transcriptional profiles from primary human breast cell types isolated from disease-free human subjects. From these data we define a comprehensive human breast transcriptional network, including a set of myoepithelial- and luminal epithelial-specific intronic retention events. Intersection of epigenetic states with RNA expression from distinct breast epithelium lineages demonstrates that mCpG provides a stable record of exonic and intronic usage, whereas H3K36me3 is dynamic. We find a striking asymmetry in epigenomic reprogramming between luminal and myoepithelial cell types, with the genomes of luminal cells harbouring more than twice the number of hypomethylated enhancer elements compared with myoepithelial cells.

Regulatory variation: an emerging vantage point for cancer biology.

Transcriptional regulation involves complex and interdependent interactions of noncoding and coding regions of the genome with proteins that interact and modify them. Genetic variation/mutation in coding and noncoding regions of the genome can drive aberrant transcription and disease. In spite of accounting for nearly 98% of the genome comparatively little is known about the contribution of noncoding DNA elements to disease. Genome-wide association studies of complex human diseases including cancer have revealed enrichment for variants in the noncoding genome. A striking finding of recent cancer genome re-sequencing efforts has been the previously underappreciated frequency of mutations in epigenetic modifiers across a wide range of cancer types. Taken together these results point to the importance of dysregulation in transcriptional regulatory control in genesis of cancer. Powered by recent technological advancements in functional genomic profiling, exploration of normal and transformed regulatory networks will provide novel insight into the initiation and progression of cancer and open new windows to future prognostic and diagnostic tools.

Recent duplications drive rapid diversification of trypsin genes in 12 Drosophila.

Trypsin participates in many fundamental biological processes, the most notably in digesting food. The 12 species of Drosophila provide a great opportunity to analyze the duplication pattern of trypsins and their association with dietary changes. Here, we find that the trypsin family expands dramatically after speciation. The duplication events are strongly related to the host preferences, with significantly more copy numbers in species breeding on rotting fruits. Temporal analysis of the duplication events indicates that the occurrences of these events are not simultaneous, but rather correlate to the ecological change or host shift. Furthermore, we find that the specialists and generalists have different adaptive selections, which is revealed by dynamic duplication and/or deletion and relatively high Ka/Ks values on the duplicated events in specialists. Our findings suggest that the duplication of trypsin genes has played an important role in the adaption of Drosophila to the diverse ecosystems.