Transcriptional corepressors in cancer

The normal cell transcriptional process entails a high degree of combinatorial effects and time‐dependent “flexibility” to translate cellular signaling into differential gene expression levels. Transcriptional corepressors can function as histone‐modifying enzymes to regulate epigenetic events, modulate chromatin structure, and hence control transcriptional activity. Various corepressor complexes have been described; qualitative and quantitative alterations of corepressors can crucially influence the transcriptional output of both normal and malignant cells. Because these molecules can exert epigenetic control of tumorigenic signaling pathways, they can be considered potential regulators of cancer cell‐related phenomena. Alterations of the expression level and/or function of transcriptional corepressors have been reported in a wide range of human cancers; thus, corepressors may present rational therapeutic targets as well as potential biomarkers of response to selective therapeutic interventions. Deeper insights into the context‐specific and time‐specific physical connections among transcription factors, coregulators, and gene regulatory elements, as well as epigenetic modifications, and their interactions, can enhance the capacity to interfere with small molecules that may restore the normal transcriptome/interactome in a cancer cell. There are several conceivable mechanisms of corepressor targeting in cancer that create enthusiasm. However, design, discovery, and testing of such innovative treatment approaches require extensive elaboration before they can achieve practical implementation in the clinic. Cancer 2013. © 2012 American Cancer Society. Alterations in the structure, expression level, and/or function of transcriptional corepressors have been documented in a broad array of human malignancies. Therefore, corepressors may function as rational therapeutic targets and/or potential biomarkers of response to selective chemotherapy regimens.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96650/1/27908_ftp.pd

Multiscale control of bacterial production by phytoplankton dynamics and sea ice along the western Antarctic Peninsula : a regional and decadal investigation

Author Posting. © The Author(s), 2012. 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 Journal of Marine Systems 98-99 (2012): 26-39, doi:10.1016/j.jmarsys.2012.03.003.We present results on phytoplankton and bacterial production and related hydrographic properties collected on nine annual summer cruises along the western Antarctic Peninsula. This region is strongly influenced by interannual variations in the duration and extent of sea ice cover, necessitating a decade-scale study. Our study area transitions from a nearshore region influenced by summer runoff from glaciers to an offshore, slope region dominated by the Antarctic Circumpolar Current. The summer bacterial assemblage is the product of seasonal warming and freshening following spring sea ice retreat and the plankton succession occurring in that evolving water mass. Bacterial production rates averaged 20 mgC m-2 d-1 and were a low (5%) fraction of the primary production (PP). There was significant variation in BP between regions and years, reflecting the variability in sea ice, Chlorophyll and PP. Leucine incorporation was significantly correlated (r2 ranging 0.2-0.7, p<0.001) with both chlorophyll and PP across depths, regions and years indicating strong phytoplankton-bacteria coupling. Relationships with temperature were variable, including positive, negative and insignificant relationships (r2 <0.2 for regressions with p<0.05). Bacterial production is regulated indirectly by variations in sea ice cover within regions and over years, setting the levels of phytoplankton biomass accumulation and PP rates; these in turn fuel BP, to which PP is coupled via direct release from phytoplankton or other less direct pathways.This research was supported by NSF Grants OPP-0217282 and 0823101 from the Antarctic Organisms and Ecosystems Program to HWD

Initial Clinical Experience of MR-Guided Radiotherapy for Non-Small Cell Lung Cancer.

Curative-intent radiotherapy plays an integral role in the treatment of lung cancer and therefore improving its therapeutic index is vital. MR guided radiotherapy (MRgRT) systems are the latest technological advance which may help with achieving this aim. The majority of MRgRT treatments delivered to date have been stereotactic body radiation therapy (SBRT) based and include the treatment of (ultra-) central tumors. However, there is a move to also implement MRgRT as curative-intent treatment for patients with inoperable locally advanced NSCLC. This paper presents the initial clinical experience of using the two commercially available systems to date: the ViewRay MRIdian and Elekta Unity. The challenges and potential solutions associated with MRgRT in lung cancer will also be highlighted

Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein

The C-terminal binding protein (CtBP) is an NADH-dependent dimeric family of nuclear proteins that scaffold interactions between transcriptional regulators and chromatin-modifying complexes. Its association with poor survival in several cancers implicates CtBP as a promising target for pharmacological intervention. We employed computer-assisted drug design to search for CtBP inhibitors, using quantitative structure-activity relationship (QSAR) modeling and docking. Functional screening of these drugs identified 4 compounds with low toxicity and high water solubility. Micro molar concentrations of these CtBP inhibitors produces significant de-repression of epigenetically silenced pro-epithelial genes, preferentially in the triple-negative breast cancer cell line MDA-MB-231. This epigenetic reprogramming occurs through eviction of CtBP from gene promoters; disrupted recruitment of chromatin-modifying protein complexes containing LSD1, and HDAC1; and re-wiring of activating histone marks at targeted genes. In functional assays, CtBP inhibition disrupts CtBP dimerization, decreases cell migration, abolishes cellular invasion, and improves DNA repair. Combinatorial use of CtBP inhibitors with the LSD1 inhibitor pargyline has synergistic influence. Finally, integrated correlation of gene expression in breast cancer patients with nuclear levels of CtBP1 and LSD1, reveals new potential therapeutic vulnerabilities. These findings implicate a broad role for this class of compounds in strategies for epigenetically targeted therapeutic intervention

Case report: Fractional brain tumor burden magnetic resonance mapping to assess response to pulsed low-dose-rate radiotherapy in newly-diagnosed glioblastoma

BackgroundPulsed low-dose-rate radiotherapy (pLDR) is a commonly used reirradiation technique for recurrent glioma, but its upfront use with temozolomide (TMZ) following primary resection of glioblastoma is currently under investigation. Because standard magnetic resonance imaging (MRI) has limitations in differentiating treatment effect from tumor progression in such applications, perfusion-weighted MRI (PWI) can be used to create fractional tumor burden (FTB) maps to spatially distinguish active tumor from treatment-related effect.MethodsWe performed PWI prior to re-resection in four patients with glioblastoma who had undergone upfront pLDR concurrent with TMZ who had radiographic suspicion for tumor progression at a median of 3 months (0-5 months or 0-143 days) post-pLDR. The pathologic diagnosis was compared to retrospectively-generated FTB maps.ResultsThe median patient age was 55.5 years (50-60 years). All were male with IDH-wild type (n=4) and O6-methylguanine-DNA methyltransferase (MGMT) hypermethylated (n=1) molecular markers. Pathologic diagnosis revealed treatment effect (n=2), a mixture of viable tumor and treatment effect (n=1), or viable tumor (n=1). In 3 of 4 cases, FTB maps were indicative of lesion volumes being comprised predominantly of treatment effect with enhancing tumor volumes comprised of a median of 6.8% vascular tumor (6.4-16.4%).ConclusionThis case series provides insight into the radiographic response to upfront pLDR and TMZ and the role for FTB mapping to distinguish tumor progression from treatment effect prior to redo-surgery and within 20 weeks post-radiation

A metagenomic assessment of winter and summer bacterioplankton from Antarctica Peninsula coastal surface waters

© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in The ISME Journal 6 (2012): 1901-1915, doi:10.1038/ismej.2012.31.Antarctic surface oceans are well-studied during summer when irradiance levels are high, sea ice is melting and primary productivity is at a maximum. Coincident with this timing, the bacterioplankton respond with significant increases in secondary productivity. Little is known about bacterioplankton in winter when darkness and sea-ice cover inhibit photoautotrophic primary production. We report here an environmental genomic and small subunit ribosomal RNA (SSU rRNA) analysis of winter and summer Antarctic Peninsula coastal seawater bacterioplankton. Intense inter-seasonal differences were reflected through shifts in community composition and functional capacities encoded in winter and summer environmental genomes with significantly higher phylogenetic and functional diversity in winter. In general, inferred metabolisms of summer bacterioplankton were characterized by chemoheterotrophy, photoheterotrophy and aerobic anoxygenic photosynthesis while the winter community included the capacity for bacterial and archaeal chemolithoautotrophy. Chemolithoautotrophic pathways were dominant in winter and were similar to those recently reported in global ‘dark ocean’ mesopelagic waters. If chemolithoautotrophy is widespread in the Southern Ocean in winter, this process may be a previously unaccounted carbon sink and may help account for the unexplained anomalies in surface inorganic nitrogen content.CSR was supported by an NSF Postdoctoral Fellowship in Biological Informatics (DBI-0532893). The research was supported by National Science Foundation awards: ANT 0632389 (to AEM and JJG), and ANT 0632278 and 0217282 (to HWD), all from the Antarctic Organisms and Ecosystems Program