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| 2. |
- Bandopadhayay, Pratiti, et al.
(författare)
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BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma
- 2014
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 20:4, s. 912-925
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.Experimental Design:We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.Results:Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index.Conclusion:JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.
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| 3. |
- Barrenäs, Fredrik, et al.
(författare)
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Deep Transcriptional Sequencing of Mucosal Challenge Compartment from Rhesus Macaques Acutely Infected with Simian Immunodeficiency Virus Implicates Loss of Cell Adhesion Preceding Immune Activation
- 2014
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Ingår i: Journal of Virology. - 0022-538X .- 1098-5514. ; 88:14, s. 7962-7972
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Tidskriftsartikel (refereegranskat)abstract
- Pathology resulting from human immunodeficiency virus (HIV) infection is driven by protracted inflammation; the primary loss of CD4(+) T cells is caused by activation-driven apoptosis. Recent studies of nonhuman primates (NHPs) have suggested that during the acute phase of infection, antiviral mucosal immunity restricts viral replication in the primary infection compartment. These studies imply that HIV achieves systemic infection as a consequence of a failure in host antiviral immunity. Here, we used high-dose intrarectal inoculation of rhesus macaques with simian immunodeficiency virus (SIV) SIVmac251 to examine how the mucosal immune system is overcome by SIV during acute infection. The host response in rectal mucosa was characterized by deep mRNA sequencing (mRNA-seq) at 3 and 12 days postinoculation (dpi) in 4 animals for each time point. While we observed a strong host transcriptional response at 3 dpi, functions relating to antiviral immunity were absent. Instead, we observed a significant number of differentially expressed genes relating to cell adhesion and reorganization of the cytoskeleton. We also observed downregulation of genes encoding members of the claudin family of cell adhesion molecules, which are coexpressed with genes associated with pathology in the colorectal mucosa, and a large number of noncoding transcripts. In contrast, at 12 dpi the differentially expressed genes were enriched in those involved with immune system functions, in particular, functions relating to T cells, B cells, and NK cells. Our findings indicate that host responses that negatively affect mucosal integrity occur before inflammation. Consequently, when inflammation is activated at peak viremia, mucosal integrity is already compromised, potentially enabling rapid tissue damage, driving further inflammation. IMPORTANCE The HIV pandemic is one of the major threats to human health, causing over a million deaths per year. Recent studies have suggested that mucosal antiviral immune responses play an important role in preventing systemic infection after exposure to the virus. Yet, despite their potential role in decreasing transmission rates between individuals, these antiviral mechanisms are poorly understood. Here, we carried out the first deep mRNA sequencing analysis of mucosal host responses in the primary infection compartment during acute SIV infection. We found that during acute infection, a significant host response was mounted in the mucosa before inflammation was triggered. Our analysis indicated that the response has a detrimental effect on tissue integrity, causing increased permeability, tissue damage, and recruitment of SIV target cells. These results emphasize the importance of mucosal host responses preceding immune activation in preventing systemic SIV infection.
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| 6. |
- Cozen, W., et al.
(författare)
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A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus
- 2014
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 3856-
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Tidskriftsartikel (refereegranskat)abstract
- Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR) = 0.81, 95% confidence interval (95% CI) = 0.76-0.86, P-combined 3.5 x 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regulator of B-and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk.
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| 8. |
- Decarli, R., et al.
(författare)
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An Alma Survey of Sub-Millimeter Galaxies in the Extended Chandra Deep Field South: Sub-Millimeter Properties of Color-Selected Galaxies
- 2014
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Ingår i: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 780:2
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Tidskriftsartikel (refereegranskat)abstract
- We study the sub-millimeter properties of color-selected galaxies via a stacking analysis applied for the first time to interferometric data at sub-millimeter wavelengths. We base our study on 344 GHz ALMA continuum observations of similar to 20 ''-wide fields centered on 86 sub-millimeter sources detected in the LABOCA Extended Chandra Deep Field South (ECDFS) Sub-millimeter Survey. We select various classes of galaxies (K-selected, star-forming sBzK galaxies, extremely red objects, and distant red galaxies) according to their optical/near-infrared fluxes. We find clear, >10 sigma detections in the stacked images of all these galaxy classes. We include in our stacking analysis Herschel/SPIRE data to constrain the dust spectral energy distribution of these galaxies. We find that their dust emission is well described by a modified blackbody with T-dust approximate to 30 K and beta = 1.6 and infrared luminosities of (5-11) x 10(11) L-circle dot or implied star formation rates of 75-140 M-circle dot yr(-1). We compare our results with those of previous studies based on single-dish observations at 870 mu m and find that our flux densities are a factor 2-3 higher than previous estimates. The discrepancy is observed also after removing sources individually detected in ALESS maps. We report a similar discrepancy by repeating our analysis on 1.4 GHz observations of the whole ECDFS. Hence, we find tentative evidence that galaxies that are associated in projected and redshift space with sub-mm bright sources are brighter than the average population. Finally, we put our findings in the context of the cosmic star formation rate density as a function of redshift.
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| 9. |
- Dekov, Vesselin, et al.
(författare)
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Ferrihydrite precipitation in goundwater-fed river systems (Nete and Demer river basins, Belgium): Insights from a combined Fe-Zn-Sr-Nd-Pb-isotope study.
- 2014
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Ingår i: Chemical Geology. - : Elsevier. - 0009-2541 .- 1872-6836. ; 386, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Two groundwater-fed river systems (Nete and Demer, Belgium) carry red suspended material that settles on the river bed forming red sediments. The local aquifer that feeds these river systems is a glauconite-rich sand, which provides most of the dissolved Fe to the rivers. The solid component of these systems, i.e., the red suspended material and sediments, has a simple mineralogy (predominantly ferrihydrite), but shows a complex geochemistry pointing out the different processes contributing to the river chemistry: (1) the red sediments have higher transition metal (excluding Cu) and detrital element (e.g., Si, Al, K, Rb, etc.) concentrations than the red suspended matter because of their longer residence time in the river and higher contribution of the background (aquifer) component, respectively; (2) the red suspended material and sediments have inherited their rare earth element (REE) patterns from the aquifer; (3) the origin of Sr present in the red suspended matter and red sediments is predominantly marine (i.e., Quaternary calcareous rocks), but a small amount is geogenic (i.e., from detrital rocks); (4) Pb in both solids originates mostly from anthropogenic and geogenic sources; (5) all of the anthropogenic Pb in the red suspended material and sediments is hosted by the ferrihydrite; (6) Nd budget of the red riverine samples is controlled by the geogenic source and shows little anthropogenic component; (7) the signi- ficant Fe- and Zn-isotope fractionations are in line with the previous studies. Their fractionation patterns do not correlate, suggesting that the processes controlling the isotope geochemistry of Fe and Zn are different: oxidation/reduction most likely governs the Fe-isotope fractionation, whereas adsorption/desorption or admixing of anthropogenic sources controls the isotope fractionation of Zn.
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| 10. |
- Greve, T. R., et al.
(författare)
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Star Formation Relations and CO-Spectral Line Energy Distributions Across the J-Ladder and Redshift
- 2014
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 794:2, s. Art. no. 142-
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Tidskriftsartikel (refereegranskat)abstract
- We present FIR [50-300 mu m]-CO luminosity relations (i.e., log L-FIR = alpha log L'(CO) + beta) for the full CO rotational ladder from J = 1-0 up to J = 13-12 for a sample of 62 local (z 10(11) L-circle dot) using data from Herschel SPIRE-FTS and ground-based telescopes. We extend our sample to high redshifts (z > 1) by including 35 submillimeter selected dusty star forming galaxies from the literature with robust CO observations, and sufficiently well-sampled FIR/submillimeter spectral energy distributions (SEDs), so that accurate FIR luminosities can be determined. The addition of luminous starbursts at high redshifts enlarge the range of the FIR-CO luminosity relations toward the high-IR-luminosity end, while also significantly increasing the small amount of mid-J/high-J CO line data (J = 5-4 and higher) that was available prior to Herschel. This new data set (both in terms of IR luminosity and J-ladder) reveals linear FIR-CO luminosity relations (i.e., a similar or equal to 1) for J = 1-0 up to J = 5-4, with a nearly constant normalization (beta similar to 2). In the simplest physical scenario, this is expected from the (also) linear FIR-(molecular line) relations recently found for the dense gas tracer lines (HCN and CS), as long as the dense gas mass fraction does not vary strongly within our (merger/starburst)-dominated sample. However, from J = 6-5 and up to the J = 13-12 transition, we find an increasingly sublinear slope and higher normalization constant with increasing J. We argue that these are caused by a warm (similar to 100 K) and dense (>10(4) cm(-3)) gas component whose thermal state is unlikely to be maintained by star-formation-powered far-UV radiation fields (and thus is no longer directly tied to the star formation rate). We suggest that mechanical heating (e.g., supernova-driven turbulence and shocks), and not cosmic rays, is the more likely source of energy for this component. The global CO spectral line energy distributions, which remain highly excited from J = 6-5 up to J = 13-12, are found to be a generic feature of the (U)LIRGs in our sample, and further support the presence of this gas component.
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