A publicly available benchmark for biomedical dataset retrieval: the reference standard for the 2016 bioCADDIE dataset retrieval challenge.

https://biocaddie.org/benchmark-data.

DATS, the data tag suite to enable discoverability of datasets.

Today's science increasingly requires effective ways to find and access existing datasets that are distributed across a range of repositories. For researchers in the life sciences, discoverability of datasets may soon become as essential as identifying the latest publications via PubMed. Through an international collaborative effort funded by the National Institutes of Health (NIH)'s Big Data to Knowledge (BD2K) initiative, we have designed and implemented the DAta Tag Suite (DATS) model to support the DataMed data discovery index.

Finding useful data across multiple biomedical data repositories using DataMed.

The value of broadening searches for data across multiple repositories has been identified by the biomedical research community. As part of the US National Institutes of Health (NIH) Big Data to Knowledge initiative, we work with an international community of researchers, service providers and knowledge experts to develop and test a data index and search engine, which are based on metadata extracted from various data sets in a range of repositories. DataMed is designed to be, for data, what PubMed has been for the scientific literature.

Suppression of RAF/MEK or PI3K synergizes cytotoxicity of receptor tyrosine kinase inhibitors in glioma tumor-initiating cells.

Background: The majority of glioblastomas have aberrant receptor tyrosine kinase (RTK)/RAS/phosphoinositide 3 kinase (PI3K) signaling pathways and malignant glioma cells are thought to be addicted to these signaling pathways for their survival and proliferation. However, recent studies suggest that monotherapies or inappropriate combination therapies using the molecular targeted drugs have limited efficacy possibly because of tumor heterogeneities, signaling redundancy and crosstalk in intracellular signaling network, indicating necessity of rationale and methods for efficient personalized combination treatments. Here, we evaluated the growth of colonies obtained from glioma tumor-initiating cells (GICs) derived from glioma sphere culture (GSC) in agarose and examined the effects of combination treatments on GICs using targeted drugs that affect the signaling pathways to which most glioma cells are addicted.

Ease of adoption of clinical natural language processing software: An evaluation of five systems.

Objective: In recognition of potential barriers that may inhibit the widespread adoption of biomedical software, the 2014 i2b2 Challenge introduced a special track, Track 3 - Software Usability Assessment, in order to develop a better understanding of the adoption issues that might be associated with the state-of-the-art clinical NLP systems. This paper reports the ease of adoption assessment methods we developed for this track, and the results of evaluating five clinical NLP system submissions.

Materials And Methods: A team of human evaluators performed a series of scripted adoptability test tasks with each of the participating systems.

Regulation of HGF expression by ΔEGFR-mediated c-Met activation in glioblastoma cells.

The hepatocyte growth factor receptor (c-Met) and a constitutively active mutant of the epidermal growth factor receptor (ΔEGFR/EGFRvIII) are frequently overexpressed in glioblastoma (GBM) and promote tumorigenesis. The mechanisms underlying elevated hepatocyte growth factor (HGF) production in GBM are not understood. We found higher, coordinated mRNA expression levels of HGF and c-Met in mesenchymal (Mes) GBMs, a subtype associated with poor treatment response and shorter overall survival.

Access to the nucleus and functional association with c-Myc is required for the full oncogenic potential of ΔEGFR/EGFRvIII.

ΔEGFR is a potent glioblastoma oncogene which has been studied primarily as a plasma membrane kinase. Using intracranial xenograft studies in mice, we show that blocking ΔEGFR access to the nucleus attenuates its tumorigenicity and, conversely, that promoting nuclear accumulation enhances this, providing the first in vivo evidence that the nuclear actions of ΔEGFR contribute strongly to its oncogenic function. Nuclear actions of ΔEGFR include regulation of gene expression by participation in chromatin-bound complexes, and genome-wide mapping of these sequences by chromatin immunoprecipitation and massively parallel sequencing identified 2294 peaks.

Inhibition of ascites tumor growth in vivo by sTie-2 is potentiated by a combinatorial therapy with sFLT-1.

Background: Inhibition of tumor angiogenesis is a promising approach for cancer therapy and the Tie-2/angiopoietin pathway appears to play an important role. In the present study, we have developed strategies to explore the therapeutic potential of blocking the Tie-2/angiopoietin pathway by sTie-2.

Methods: Ehrlich ascites tumor (EAT) cells were stably transfected to overexpress a truncated form of sTie-2.

Acetylation-dependent oncogenic activity of metastasis-associated protein 1 co-regulator.

High expression of metastasis-associated protein 1 co-regulator (MTA1), a component of the nuclear remodelling and histone deacetylase complex, has been associated with human tumours. However, the precise role of MTA1 in tumorigenesis remains unknown. In this study, we show that induced levels of MTA1 are sufficient to transform Rat1 fibroblasts and that the transforming potential of MTA1 is dependent on its acetylation at Lys626.

Paracrine action of sFLT-1 secreted by stably-transfected Ehrlich ascites tumor cells and therapy using sFLT-1 inhibits ascites tumor growth in vivo.

Background: Vascular endothelial growth factor (VEGF) is known to play a major role in angiogenesis. A soluble form of Flt-1, a VEGF receptor, is potentially useful as an antagonist of VEGF, and accumulating evidence suggests the applicability of sFlt-1 in tumor suppression. In the present study, we have developed and tested strategies targeted specifically to VEGF for the treatment of ascites formation.

Identification of Pax5 as a target of MTA1 in B-cell lymphomas.

Previously, we have shown that metastasis-associated protein 1 (MTA1) overexpression in transgenic mice was accompanied by high incidence of spontaneous B-cell lymphomas including diffuse large B-cell lymphomas (DLBCL). To understand the molecular basis of lymphoma in MTA1-transgenic (MTA1-TG) mice, we wished to identify a putative MTA1 target with a causal role in B-cell lymphogenesis. Using chromatin immunoprecipitation assays, we identified paired box gene 5 (Pax5), a molecule previously implicated in B-cell lymphogenesis, as a potential downstream effector of MTA1.

Metastasis-associated protein 1 transgenic mice: a new model of spontaneous B-cell lymphomas.

Metastasis-associated protein 1 (MTA1), a component of the nuclear remodeling complex and the founding homologue of the MTA family, has been implicated in metastasis, but definitive causative evidence in an animal model system is currently lacking. Here, we show that MTA1 overexpression in transgenic mice is accompanied by a high incidence of spontaneous B cell lymphomas including diffuse large B cell lymphomas (DLBCL). Lymphocytes and lymphoma cells from MTA1-TG mice are hyperproliferative.

Estrogen induces expression of BCAS3, a novel estrogen receptor-alpha coactivator, through proline-, glutamic acid-, and leucine-rich protein-1 (PELP1).

We recently reported that the breast carcinoma amplified sequence-3 (BCAS3) gene is regulated by estrogen receptor (ER) alpha. However, the role of ERalpha coactivators in the regulation of BCAS3 expression remains unknown, and information regarding the function of the BCAS3 protein is lacking. Here, we define the contribution of ERalpha coactivators to BCAS3 regulation and identify BCAS3 itself as an ERalpha coactivator in breast cancer cells.

Signaling-dependent and coordinated regulation of transcription, splicing, and translation resides in a single coregulator, PCBP1.

Transcription, splicing, and translation are potentially coordinately regulatable in a temporospatial-dependent manner, although supporting experimental evidence for this notion is scarce. Yeast two-hybrid screening of a mammary gland cDNA library with human p21-activated kinase 1 (Pak1) as bait identified polyC-RNA-binding protein 1 (PCBP1), which controls translation from mRNAs containing the DICE (differentiation control element). Mitogenic stimulation of human cells phosphorylated PCBP1 on threonines 60 and 127 in a Pak1-sensitive manner.

Breast cancer-amplified sequence 3, a target of metastasis-associated protein 1, contributes to tamoxifen resistance in premenopausal patients with breast cancer.

Lysine acetylation occurs in many protein targets, including core histones, transcription factors, and other proteins. Metastasis-associated protein 1 (MTA1) is implicated in the progression and metastasis of various epithelial tumors. Because MTA1 functions as a transcriptional coregulator, much of its role in cancer promoting processes are likely to involve its ability to regulate the transcription of downstream target genes that encode effector proteins.

p21-activated kinases in cancer.

The pivotal role of kinases in signal transduction and cellular regulation has lent them considerable appeal as pharmacological targets across a broad spectrum of cancers. p21-activated kinases (Paks) are serine/threonine kinases that function as downstream nodes for various oncogenic signalling pathways. Paks are well-known regulators of cytoskeletal remodelling and cell motility, but have recently also been shown to promote cell proliferation, regulate apoptosis and accelerate mitotic abnormalities, which results in tumour formation and cell invasiveness.

MTA1, a transcriptional activator of breast cancer amplified sequence 3.

Here we define a function of metastasis-associated protein 1 (MTA1), a presumed corepressor of estrogen receptor alpha (ERalpha), as a transcriptional activator of Breast Cancer Amplified Sequence 3 (BCAS3), a gene amplified and overexpressed in breast cancers. We identified BCAS3 as a MTA1 chromatin target in a functional genomic screen. MTA1 stimulation of BCAS3 transcription required ERalpha and involved a functional ERE half-site in BCAS3.

9-cis-retinoic acid up-regulates expression of transcriptional coregulator PELP1, a novel coactivator of the retinoid X receptor alpha pathway.

Retinoid X receptor alpha (RXRalpha), functioning as either a homodimer or a heterodimer with peroxisome proliferator receptors, is known to be involved in manifesting antiproliferative effects in cells. Consequently, studies of RXRalpha functions and its coregulators have been in the focus for therapeutic approaches against cancer. Here we have discovered that 9-cis-retinoic acid (9-cis-RA), a RXRalpha-specific ligand, up-regulated the expression of transcriptional coregulatory protein PELP1 (proline-, glutamic acid-, and leucine-rich protein 1).

Novel mechanisms of resistance to endocrine therapy: genomic and nongenomic considerations.

Selective estrogen receptor (ER) modulators have been the most commonly used neoadjuvant therapy for hormone-dependent breast cancer. However, resistance to endocrine therapy, either inherent or acquired during treatment, presents a major challenge in disease management. The causes of resistance to hormone therapy are not well understood and are the subject of active investigation.

The clinical relevance of steroid hormone receptor corepressors.

Steroid hormone receptors are ligand-dependent transcription factors that control a variety of essential physiologic and developmental processes in humans. The functional activity of a steroid receptor is regulated not only by hormones but also by an array of regulatory proteins such as coactivators, corepressors, and chromatin modifiers. Contrary to an earlier notion that corepressors and coactivators exist in separate complexes, these molecules, which have apparently opposite functions, are increasingly being found in the same complex, which allows for efficient transcriptional control mechanisms.

p21-activated kinase signaling in breast cancer.

The p21-activated kinases signal through a number of cellular pathways fundamental to growth, differentiation and apoptosis. A wealth of information has accumulated at an impressive pace in the recent past, both with regard to previously identified targets for p21-activated kinases that regulate the actin cytoskeleton and cellular stress pathways and with regard to newly identified targets and their role in cancer. Emerging data also provide new clues towards a previously unappreciated link between these various cellular processes.

Upstream determinants of estrogen receptor-alpha regulation of metastatic tumor antigen 3 pathway.

Although recent studies have shown a role of estrogen receptor-alpha (ER) in the regulation of epithelial-to-mesenchymal transition via MTA3, the role of upstream determinants of ER regulation of MTA3 and the underlying molecular mechanism remains unknown. Here we show that MTA3 gene regulation by ER is influenced by dynamic changes in levels of nuclear coregulators. MTA3 promoter has a functional ER element half-site with which MTA1 and HDACs interact under basal conditions.