Predicting carcinogenicity by using batteries of dependent short-term tests.

Among the various methods for predicting carcinogenicity from a battery of short-term tests (STTs), the carcinogenicity prediction and battery selection (CPBS) procedure is the most prominent. A major assumption of CPBS is that the STTs used in the prediction are conditionally independent. Results of recent National Toxicology Program studies of four commonly used in vitro STTs contradict this assumption, thereby necessitating modification of CPBS to accommodate dependencies. This is accomplished via log-linear modeling, which then also yields an important dividend: standard errors for the predicted probabilities of carcinogenicity

ChIP-on-chip significance analysis reveals large-scale binding and regulation by human transcription factor oncogenes

ChIP-on-chip has emerged as a powerful tool to dissect the complex network of regulatory interactions between transcription factors and their targets. However, most ChIP-on-chip analysis methods use conservative approaches aimed to minimize false-positive transcription factor targets. We present a model with improved sensitivity in detecting binding events from ChIP-on-chip data. Biochemically validated analysis in human T-cells reveals that three transcription factor oncogenes, NOTCH1, MYC, and HES1, bind one order of magnitude more promoters than previously thought. Gene expression profiling upon NOTCH1 inhibition shows broad-scale functional regulation across the entire range of predicted target genes, establishing a closer link between occupancy and regulation. Finally, the resolution of a more complete map of transcriptional targets reveals that MYC binds nearly all promoters bound by NOTCH1. Overall, these results suggest an unappreciated complexity of transcriptional regulatory networks and highlight the fundamental importance of genome-scale analysis to represent transcriptional programs

Phase 2 study of RO4929097, a gamma‐secretase inhibitor, in metastatic melanoma: SWOG 0933

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110565/1/cncr29055.pd

CABARET in the ocean gyres

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Ocean Modelling 30 (2009): 155-168, doi:10.1016/j.ocemod.2009.06.009.A new high-resolution Eulerian numerical method is proposed for modelling quasigeostrophic ocean dynamics in eddying regimes. The method is based on a novel, second-order non-dissipative and lowdispersive conservative advection scheme called CABARET. The properties of the new method are compared with those of several high-resolution Eulerian methods for linear advection and gas dynamics. Then, the CABARET method is applied to the classical model of the double-gyre ocean circulation and its performance is contrasted against that of the common vorticity-preserving Arakawa method. In turbulent regimes, the new method permits credible numerical simulations on much coarser computational grids.Supports from the Royal Society of London and from the Mary Sears Visitor Grant are acknowledged by SK with gratitude. The work of VG was supported by the Russian Foundation for Basic Research (RFBR), grant 06-01-00819a. Funding for PB was provided by the NSF grant 0725796

Updates in the management of brain metastases

The clinical management/understanding of brain metastases (BM) has changed substantially in the last 5 years, with key advances and clinical trials highlighted in this review. Several of these changes stem from improvements in systemic therapy, which have led to better systemic control and longer overall patient survival, associated with increased time at risk for developing BM. Development of systemic therapies capable of preventing BM and controlling both intracranial and extracranial disease once BM are diagnosed is paramount. The increase in use of stereotactic radiosurgery alone for many patients with multiple BM is an outgrowth of the desire to employ treatments focused on local control while minimizing cognitive effects associated with whole brain radiotherapy. Complications from BM and their treatment must be considered in comprehensive patient management, especially with greater awareness that the majority of patients do not die from their BM. Being aware of significant heterogeneity in prognosis and therapeutic options for patients with BM is crucial for appropriate management, with greater attention to developing individual patient treatment plans based on predicted outcomes; in this context, recent prognostic models of survival have been extensively revised to incorporate molecular markers unique to different primary cancers

Cancer cells exploit an orphan RNA to drive metastatic progression.

Here we performed a systematic search to identify breast-cancer-specific small noncoding RNAs, which we have collectively termed orphan noncoding RNAs (oncRNAs). We subsequently discovered that one of these oncRNAs, which originates from the 3' end of TERC, acts as a regulator of gene expression and is a robust promoter of breast cancer metastasis. This oncRNA, which we have named T3p, exerts its prometastatic effects by acting as an inhibitor of RISC complex activity and increasing the expression of the prometastatic genes NUPR1 and PANX2. Furthermore, we have shown that oncRNAs are present in cancer-cell-derived extracellular vesicles, raising the possibility that these circulating oncRNAs may also have a role in non-cell autonomous disease pathogenesis. Additionally, these circulating oncRNAs present a novel avenue for cancer fingerprinting using liquid biopsies