Recently, there have been studies on the projection from the entopeduncular nucleus (EP) to the lateral habenula (LHb) and its relationship to the reward and disappointment systems. Specifically, the projection from the EP to the LHb have been found to be excitatory and behaviorally aversive in rats. However, the response to pain in the projection from the EP to the LHb has not yet been studied or identified. Here, we find that many neurons are initially excited, then inhibited in both the EP and LHb, but only the EP has a large proportion of cells that are only inhibited after the shock. We also found that the majority of inhibited EP cells had high baseline firing rates, whereas the majority of LHb neurons with high baseline firing rates were excited by tailshock. These results suggest that there at least two populations of cells in the EP that project to the LHb and are activated by shock. One population sends excitatory projections to the LHb and is excited initially, then inhibited by shock. The other population sends inhibitory projections to the LHb and is only inhibited by shock

BACKGROUND: The objective of this study was to demonstrate that computer-extracted image phenotypes (CEIPs) of biopsy-proven breast cancer on magnetic resonance imaging (MRI) can accurately predict pathologic stage. METHODS: The authors used a data set of deidentified breast MRIs organized by the National Cancer Institute in The Cancer Imaging Archive. In total, 91 biopsy-proven breast cancers were analyzed from patients who had information available on pathologic stage (stage I, n = 22; stage II, n = 58; stage III, n = 11) and surgically verified lymph node status (negative lymph nodes, n = 46; ≥ 1 positive lymph node, n = 44; no lymph nodes examined, n = 1). Tumors were characterized according to 1) radiologist-measured size and 2) CEIP. Then, models were built that combined 2 CEIPs to predict tumor pathologic stage and lymph node involvement, and the models were evaluated in a leave-1-out, cross-validation analysis with the area under the receiver operating characteristic curve (AUC) as the value of interest. RESULTS: Tumor size was the most powerful predictor of pathologic stage, but CEIPs that captured biologic behavior also emerged as predictive (eg, stage I and II vs stage III demonstrated an AUC of 0.83). No size measure was successful in the prediction of positive lymph nodes, but adding a CEIP that described tumor homogeneity significantly improved discrimination (AUC = 0.62; P = .003) compared with chance. CONCLUSIONS: The current results indicate that MRI phenotypes have promise for predicting breast cancer pathologic stage and lymph node status. Cancer 2016;122:748-757. © 2015 American Cancer Society.

Unlabelled

ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. In this article, we report a key function of ARID1A in regulating the DNA damage checkpoint. ARID1A is recruited to DNA double-strand breaks (DSB) via its interaction with the upstream DNA damage checkpoint kinase ATR. At the molecular level, ARID1A facilitates efficient processing of DSB to single-strand ends and sustains DNA damage signaling. Importantly, ARID1A deficiency sensitizes cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with ARID1A-mutant tumors.

Significance

ARID1A has been identified as one of the most frequently mutated genes across human cancers. Our data suggest that clinical utility of PARP inhibitors might be extended beyond patients with BRCA mutations to a larger group of patients with ARID1A-mutant tumors, which may exhibit therapeutic vulnerability to PARP inhibitors.

Numerous DNA repair and signaling proteins function at DNA damage sites to protect the genome. Here, we show that fusion of the promiscuous biotin ligase BirAR118G with RAD18 leads to localized protein biotinylation at DNA damage sites, allowing identification of ZPET (zinc finger protein proximal to RAD eighteen)/ZNF280C as a potential DNA damage response (DDR) protein. ZPET binds ssDNA and localizes to DNA double-strand breaks (DSBs) and stalled replication forks. In vitro, ZPET inhibits MRE11 binding to ssDNA. In cells, ZPET delays MRE11 binding to chromatin after DSB formation and slows DNA end resection through binding ssDNA. ZPET hinders resection independently of 53BP1 and HELB. Cells lacking ZPET displayed enhanced homologous recombination (HR), accelerated replication forks under stress, and increased resistance to DSBs and PARP inhibition. These results not only reveal ZPET as an HR repressor but also suggest that localized protein biotinylation at DNA damage sites is a useful strategy to identify DDR proteins.

Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The DACH1 gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Herein, DACH1 gene deletion within the 13q21.31-q21.33 region occurs in up to 18% of human PCa and was associated with increased AR activity and poor prognosis. In prostate OncoMice, prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN), and was associated with increased TGFβ activity and DNA damage. Reduced Dach1 increased DNA damage in response to genotoxic stresses. DACH1 was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced Dach1 expression was associated with increased homology directed repair and resistance to PARP inhibitors and TGFβ kinase inhibitors. Reduced Dach1 expression may define a subclass of PCa that warrants specific therapies.

The BIG Data Center at Beijing Institute of Genomics (BIG) of the Chinese Academy of Sciences provides a suite of database resources in support of worldwide research activities in both academia and industry. With the vast amounts of multi-omics data generated at unprecedented scales and rates, the BIG Data Center is continually expanding, updating and enriching its core database resources through big data integration and value-added curation. Resources with significant updates in the past year include BioProject (a biological project library), BioSample (a biological sample library), Genome Sequence Archive (GSA, a data repository for archiving raw sequence reads), Genome Warehouse (GWH, a centralized resource housing genome-scale data), Genome Variation Map (GVM, a public repository of genome variations), Science Wikis (a catalog of biological knowledge wikis for community annotations) and IC4R (Information Commons for Rice). Newly released resources include EWAS Atlas (a knowledgebase of epigenome-wide association studies), iDog (an integrated omics data resource for dog) and RNA editing resources (for editome-disease associations and plant RNA editosome, respectively). To promote biodiversity and health big data sharing around the world, the Open Biodiversity and Health Big Data (BHBD) initiative is introduced. All of these resources are publicly accessible at http://bigd.big.ac.cn.