Identification of novel prognostic indicators for triple-negative breast cancer patients through integrative analysis of cancer genomics data and protein interactome data.

Triple negative breast cancers (TNBCs) are highly heterogeneous and aggressive without targeted treatment. Here, we aim to systematically dissect TNBCs from a prognosis point of view by building a subnetwork atlas for TNBC prognosis through integrating multi-dimensional cancer genomics data from The Cancer Genome Atlas (TCGA) project and the interactome data from three different interaction networks. The subnetworks are represented as the protein-protein interaction modules perturbed by multiple genetic and epigenetic interacting mechanisms contributing to patient survival. Predictive power of these subnetwork-derived prognostic models is evaluated using Monte Carlo cross-validation and the concordance index (C-index). We uncover subnetwork biomarkers of low oncogenic GTPase activity, low ubiquitin/proteasome degradation, effective protection from oxidative damage, and tightly immune response are linked to better prognosis. Such a systematic approach to integrate massive amount of cancer genomics data into clinical practice for TNBC prognosis can effectively dissect the molecular mechanisms underlying TNBC patient outcomes and provide potential opportunities to optimize treatment and develop therapeutics.

Structure-guided optimization of small molecules inhibiting human immunodeficiency virus 1 Tat association with the human coactivator p300/CREB binding protein-associated factor.

Human immunodeficiency virus 1 (HIV-1) trans-activator Tat recruits the human transcriptional coactivator PCAF (p300/CREB binding protein-associated factor) to facilitate transcription of the integrated HIV-1 provirus. We report here structure-based lead optimization of small-molecule inhibitors that block selectively Tat and PCAF association in cells. Our lead optimization was guided by grand-canonical ensemble simulation of the receptor/lead complex that leads to definition of chemical modifications with improved lead affinity through displacing weakly bound water molecules at the ligand-receptor interface.