Clinical significance of Polycomb gene expression in brain tumors

Polycomb group (PcG) proteins are crucial for neural cancer stem cell (NCSC) self-renewal. However, the relative expression levels of PcG genes in different subtypes of brain tumors, their prognostic role and their effects on cellular pathways have not been investigated. For this purpose, we queried the Oncomine database and found that 4 PcG genes (EZH2, RBBP7, SUZ12, YY1) are specifically expressed in brain tumors. EZH2 expression increases with tumor grade in adult and pediatric brain tumors, and is a poor prognostic factor. In glioblastoma, EZH2 inhibits differentiation, and activates cancer-, cell cycle- and cellular movement-related genes. In keeping with previously published data, our results suggest that EZH2 is both a prognostic factor and a promising therapy target in brain tumors

Microinjected cDNA encoding JAK2 protein-tyrosine kinase induces DNA synthesis in NIH3T3 cells 1The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.By acceptance of this article, the publisher or recipient acknowledges right of the US Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.1

AbstractMicroinjection of expression plasmids encoding either JAK2 or hyperactive (NΔ661)rJAK2 into serum-starved NIH3T3 cells resulted in 20–30-fold induction of DNA synthesis. Control microinjections of buffer or parental pcDNA3 vector resulted in only 3–5-fold induction of DNA synthesis. Induction of DNA synthesis was blocked when plasmid encoding JAK2 was microinjected in the presence of the JAK2-selective inhibitor AG-490, whereas AG-490 did not block DNA synthesis induced by microinjected plasmid encoding (NΔ661)rJAK2. The ability of JAK2 to initiate the Go/S cell cycle transition is comparable to that of other proto-oncogenes, and supports a mechanistic role for overexpressed Janus kinases in carcinogenesis

Genomic profiling of tumor initiating prostatospheres

<p>Abstract</p> <p>Background</p> <p>The cancer stem cell (CSC) hypothesis proposes that a population of tumor cells bearing stem cell properties is responsible for the origin and maintenance of tumors. Normal and cancer stem cells possess the ability to grow in vitro as self-renewing spheres, but the molecular basis of this phenotype remains largely unknown. We intended to establish a comprehensive culture system to grow prostatospheres (PSs) from both cancer cell lines and patient tumors. We then used gene expression microarrays to gain insight on the molecular pathways that sustain the PS tumor initiating cell (TIC) phenotype.</p> <p>Results</p> <p>Traditional stem cell medium (SCM) supplemented with Knockout™SR (KO) allows the propagation of monoclonal PSs from cell lines and primary cells. PSs display gene expression and tumorigenicity hallmarks of TICs. Gene expression analysis defined a gene signature composed of 66 genes that characterize LNCaP and patient PSs. This set includes novel prostate TIC growth factors (NRP1, GDF1, JAG1), proteins implicated in cell adhesion and cytoskeletal maintenance, transcriptional regulators (MYCBP, MYBL1, ID1, ID3, FOS, ELF3, ELF4, KLF2, KLF5) and factors involved in protein biosynthesis and metabolism. Meta-analysis in Oncomine reveals that some of these genes correlate with prostate cancer status and/or progression. Reporter genes and inhibitors indicate that the Notch pathway contributes to prostatosphere growth.</p> <p>Conclusions</p> <p>We have developed a model for the culture of PSs, and provide a genomic profile that support CSCs identity. This signature identifies novel markers and pathways that are predicted to correlate with prostate cancer evolution.</p

Pharmacologic disruption of Polycomb Repressive Complex 2 inhibits tumorigenicity and tumor progression in prostate cancer

<p>Abstract</p> <p>Background</p> <p>Polycomb repressive complex 2 (PRC2) mediates gene silencing through histone H3K27 methylation. PRC2 components are over-expressed in metastatic prostate cancer (PC), and are required for cancer stem cell (CSC) self-renewal. 3-Dezaneplanocin-A (DZNeP) is an inhibitor of PRC2 with broad anticancer activity.</p> <p>Method</p> <p>we investigated the effects of DZNeP on cell proliferation, tumorigenicity and invasive potential of PC cell lines (LNCaP and DU145).</p> <p>Results</p> <p>Exploring GEO and Oncomine databases, we found that specific PRC2 genes (EED, EZH2, SUZ12) predict poor prognosis in PC. Non-toxic DZNeP concentrations completely eradicated LNCaP and DU145 prostatosphere formation, and significantly reduced the expression of CSC markers. At comparable doses, other epigenetic drugs were not able to eradicate CSCs. DZNeP was also able to reduce PC cell invasion. Cells pre-treated with DZNeP were significantly less tumorigenic (LNCaP) and formed smaller tumors (DU145) in immunocompromised mice.</p> <p>Conclusion</p> <p>DZNeP is effective both in vitro and in vivo against PC cells. DZNeP antitumor activity is in part mediated by inhibition of CSC tumorigenic potential.</p

From salty to fresh—salinity processes in the Upper-ocean Regional Study-2 (SPURS-2) : diagnosing the physics of a rainfall-dominated salinity minimum

Author Posting. © The Oceanography Society, 2015. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 28, no. 1 (2015): 150-159, doi:10.5670/oceanog.2015.15.One of the notable features of the global ocean is that the salinity of the North Atlantic is about 1 psu higher than that of the North Pacific. This contrast is thought to be due to one of the large asymmetries in the global water cycle: the transport of water vapor by the trade winds across Central America and the lack of any comparable transport into the Atlantic from the Sahara Desert. Net evaporation serves to maintain high Atlantic salinities, and net precipitation lowers those in the Pacific. Because the effects on upper-ocean physics are markedly different in the evaporating and precipitating regimes, the next phase of research in the Salinity Processes in the Upper-ocean Regional Study (SPURS) must address a high rainfall region. It seemed especially appropriate to focus on the eastern tropical Pacific that is freshened by the water vapor carried from the Atlantic. In a sense, the SPURS-2 Pacific region will be looking at the downstream fate of the freshwater carried out of the SPURS-1 North Atlantic region. Rainfall tends to lower surface density and thus inhibit vertical mixing, leading to quite different physical structure and dynamics in the upper ocean. Here, we discuss the motivations for the location of SPURS-2 and the scientific questions we hope to address

Disruption of estrogen receptor DNA-binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer

SummaryA serious obstacle to successful treatment of estrogen receptor (ER)-positive human breast cancer is cell resistance to tamoxifen (TAM) therapy. Here we show that the electrophile disulfide benzamide (DIBA), an ER zinc finger inhibitor, blocks ligand-dependent and -independent cell growth of TAM-resistant breast cancer in vitro and in vivo. Such inhibition depends on targeting disruption of the ER DNA-binding domain and its communication with neighboring functional domains, facilitating ERα dissociation from its coactivator AIB1 and concomitant association with its corepressor NCoR bound to chromatin. DIBA does not affect phosphorylation of HER2, MAPK, AKT, and AIB1, suggesting that DIBA-modified ERα may induce a switch from agonistic to antagonistic effects of TAM on resistant breast cancer cells

Did the evidence-based intervention (EBI) programme reduce inappropriate procedures, lessen unwarranted variation or lead to spill-over effects in the National Health Service?

Background Health systems are under pressure to maintain services within limited resources. The Evidence-Based Interventions (EBI) programme published a first list of guidelines in 2019, which aimed to reduce inappropriate use of interventions within the NHS in England, reducing potential harm and optimising the use of limited resources. Seventeen procedures were selected in the first round, published in April 2019. Methods We evaluated changes in the trends for each procedure after its inclusion in the EBI’s first list of guidelines using interrupted time series analysis. We explored whether there was any evidence of spill-over effects onto related or substitute procedures, as well as exploring changes in geographical variation following the publication of national guidance. Results Most procedures were experiencing downward trends in the years prior to the launch of EBI. We found no evidence of a trend change in any of the 17 procedures following the introduction of the guidance. No evidence of spill-over increases in substitute or related procedures was found. Geographic variation in the number of procedures performed across English CCGs remained at similar levels before and after EBI. Conclusions The EBI programme had little success in its aim to further reduce the use of the 17 procedures it deemed inappropriate in all or certain circumstances. Most procedure rates were already decreasing before EBI and all continued with a similar trend afterwards. Geographical variation in the number of procedures remained at a similar level post EBI. De-adoption of inappropriate care is essential in maintaining health systems across the world. However, further research is needed to explore context specific enablers and barriers to effective identification and de-adoption of such inappropriate health care to support future de-adoption endeavours

Did the evidence-based intervention (EBI) programme reduce inappropriate procedures, lessen unwarranted variation or lead to spill-over effects in the National Health Service?

Background: Health systems are under pressure to maintain services within limited resources. The Evidence-Based Interventions (EBI) programme published a first list of guidelines in 2019, which aimed to reduce inappropriate use of interventions within the NHS in England, reducing potential harm and optimising the use of limited resources. Seventeen procedures were selected in the first round, published in April 2019. Methods: We evaluated changes in the trends for each procedure after its inclusion in the EBI’s first list of guidelines using interrupted time series analysis. We explored whether there was any evidence of spill-over effects onto related or substitute procedures, as well as exploring changes in geographical variation following the publication of national guidance. Results: Most procedures were experiencing downward trends in the years prior to the launch of EBI. We found no evidence of a trend change in any of the 17 procedures following the introduction of the guidance. No evidence of spill-over increases in substitute or related procedures was found. Geographic variation in the number of procedures performed across English CCGs remained at similar levels before and after EBI. Conclusions: The EBI programme had little success in its aim to further reduce the use of the 17 procedures it deemed inappropriate in all or certain circumstances. Most procedure rates were already decreasing before EBI and all continued with a similar trend afterwards. Geographical variation in the number of procedures remained at a similar level post EBI. De-adoption of inappropriate care is essential in maintaining health systems across the world. However, further research is needed to explore context specific enablers and barriers to effective identification and de-adoption of such inappropriate health care to support future de-adoption endeavours

Autonomous multi-platform observations during the Salinity Processes in the Upper-ocean Regional Study

Author Posting. © The Oceanography Society, 2017. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 30, no. 2 (2017): 38–48, doi:10.5670/oceanog.2017.218.The Salinity Processes in the Upper-ocean Regional Study (SPURS) aims to understand the patterns and variability of sea surface salinity. In order to capture the wide range of spatial and temporal scales associated with processes controlling salinity in the upper ocean, research vessels delivered autonomous instruments to remote sites, one in the North Atlantic and one in the Eastern Pacific. Instruments sampled for one complete annual cycle at each of these two sites, which are subject to contrasting atmospheric forcing. The SPURS field programs coordinated sampling from many different platforms, using a mix of Lagrangian and Eulerian approaches. This article discusses the motivations, implementation, and first results of the SPURS-1 and SPURS-2 programs.SPURS is supported by multiple NASA grants, with important additional contributions from the US National Science Foundation, NOAA, and the Office of Naval Research, as well as international agencies. SVP drifters are deployed with support from NASA and the NOAA funded Global Drifter Program at the Lagrangian Drifter Laboratory of the Scripps Institution of Oceanography. SVP-S2 drifters are provided by NOAA-AOML and NASA. PRAWLER mooring development is supported by NOAA’s Office of Oceanic and Atmospheric Research, Ocean Observing and Monitoring Division, and by NOAA/PMEL