Identifizierung VHL-assoziierter Veränderungen im klarzelligen Nierenzellkarzinom: Anwendung von kombinierten Genom- und Expressionsanalysen

Zusammenfassung: Das sporadische Nierenzellkarzinom (NZK) ist ein heterogener solider Tumor, der traditionell basierend auf morphologischen Kriterien in weitere Subtypen unterteilt wird. In den letzten Jahren konnten unter Anwendung molekularer Hochdurchsatzanalysen genetische, transkriptionelle und translationale Alterationen identifiziert werden. Diese Marker eignen sich zum einen für die molekulare Klassifizierung des NZK und haben zum anderen prognostische Wertigkeit. Die isolierte Betrachtung genetischer, transkriptioneller und translationaler Veränderungen verhindert jedoch ein tieferes Verständnis für die komplexen Vorgänge der Karzinogenese. Wir fassen hier aktuelle Forschungsergebnisse zur molekularen Charakterisierung des NZK zusammen und stellen ein systembiologisches Konzept zur Identifizierung neuer Tumormarker vor. Diese könnten zukünftig Einsatz in der Diagnostik und Therapie des sporadischen NZK finde

Von-Hippel-Lindau-Gen-Mutationstypen: Assoziation mit Genexpressionssignaturen in klarzelligen Nierenzellkarzinomen

Zusammenfassung: Fragestellung: Der Von-Hippel-Lindau- (VHL-)Tumorsuppressor ist ein multifunktionelles Protein. VHL-Mutationen treten häufig auf im klarzelligen Nierenzellkarzinom (kNZK). Verschiedene Mutationstypen führen vermutlich zu spezifischen pVHL-Funktionsveränderungen, die wiederum einen signifikanten Einfluss auf die Genexpression und schließlich auf den Krankheitsverlauf haben dürften. Ziel der vorliegenden Studie ist die Korrelation von Genexpressionssignaturen mit spezifischen VHL-Mutationstypen im kNZK. Methodik: Transkriptomanalyse wurde für 94 kNZK und 21 papilläre NZK (pNZK) mittels Affymetrix HG U133A Genchips durchgeführt. Alle 94 kNZK wurden auf VHL-Mutationen analysiert. Ergebnisse: Ein "hierarchical clustering" anhand der zwischen kNZK und pNZK differenziell regulierten Gene zeigt eine deutliche Stratifizierung der beiden histologischen Subtypen. 186 Gene wurden zwischen VHL-Wildtyp kNZK und kNZK mit mutiertem VHL-Gen differenziell exprimiert. Schlussfolgerung: Unsere Resultate weisen auf eine signifikante Auswirkung von VHL-Mutationen auf die Genexpression im NZK hi

The host galaxies of three radio-loud quasars: 3C 48, 3C 345, and B2 1425+267

Observations with the Wide-Field/Planetary Camera-2 of the Hubble Space Telescope (HST) are presented for three radio-loud quasars: 3C 48 (z=0.367), B2 1425+267 (z=0.366), and 3C 345 (z=0.594). All three quasars have luminous (~4 L^*) galaxies as hosts, which are either elliptical (B2 1425+267 and 3C 345) or interacting (3C 48), and all hosts are 0.5 - 1.0 mag bluer in (V-I) than other galaxies with the same overall morphology at similar redshifts to the quasars. The host of 3C 48 has many H II regions and a very extended tidal tail. All nine of the radio-loud quasars studied here and in Bahcall et al. (1997) either have bright elliptical hosts or occur in interacting systems. There is a robust correlation between the radio emission of the quasar and the luminosity of host galaxy; the radio-loud quasars reside in galaxies that are on average about 1 mag brighter than hosts of the radio-quiet quasars.Comment: Accepted for publication in ApJ. 3 postscript and 3 jpeg figures. Original figures may be found in ftp://eku.sns.ias.edu/pub/sofia/RadioLoud

Reduction of time-resolved space-based CCD photometry developed for MOST Fabry Imaging data

The MOST (Microvariability & Oscillations of STars) satellite obtains ultraprecise photometry from space with high sampling rates and duty cycles. Astronomical photometry or imaging missions in low Earth orbits, like MOST, are especially sensitive to scattered light from Earthshine, and all these missions have a common need to extract target information from voluminous data cubes. They consist of upwards of hundreds of thousands of two-dimensional CCD frames (or sub-rasters) containing from hundreds to millions of pixels each, where the target information, superposed on background and instrumental effects, is contained only in a subset of pixels (Fabry Images, defocussed images, mini-spectra). We describe a novel reduction technique for such data cubes: resolving linear correlations of target and background pixel intensities. This stepwise multiple linear regression removes only those target variations which are also detected in the background. The advantage of regression analysis versus background subtraction is the appropriate scaling, taking into account that the amount of contamination may differ from pixel to pixel. The multivariate solution for all pairs of target/background pixels is minimally invasive of the raw photometry while being very effective in reducing contamination due to, e.g., stray light. The technique is tested and demonstrated with both simulated oscillation signals and real MOST photometry.Comment: 16 pages, 23 figure

Synthetic transactivation screening reveals ETV4 as broad coactivator of hypoxia-inducible factor signaling

The human prolyl-4-hydroxylase domain (PHD) proteins 1-3 are known as cellular oxygen sensors, acting via the degradation of hypoxia-inducible factor (HIF) α-subunits. PHD2 and PHD3 genes are inducible by HIFs themselves, suggesting a negative feedback loop that involves PHD abundance. To identify novel regulators of the PHD2 gene, an expression array of 704 transcription factors was screened by a method that allows distinguishing between HIF-dependent and HIF-independent promoter regulation. Among others, the E-twenty six transcription factor ETS translocation variant 4 (ETV4) was found to contribute to PHD2 gene expression particularly under hypoxic conditions. Mechanistically, complex formation between ETV4 and HIF-1/2α was observed by mammalian two-hybrid and fluorescence resonance energy transfer analysis. HIF-1α domain mapping, CITED2 overexpression and factor inhibiting HIF depletion experiments provided evidence for cooperation between HIF-1α and p300/CBP in ETV4 binding. Chromatin immunoprecipitation confirmed ETV4 and HIF-1α corecruitment to the PHD2 promoter. Of 608 hypoxically induced transcripts found by genome-wide expression profiling, 7.7% required ETV4 for efficient hypoxic induction, suggesting a broad role of ETV4 in hypoxic gene regulation. Endogenous ETV4 highly correlated with PHD2, HIF-1/2α and several established markers of tissue hypoxia in 282 human breast cancer tissue samples, corroborating a functional interplay between the ETV4 and HIF pathway

An interleukin-1 polymorphism additionally intensified by atopy as prognostic factor for aseptic non-mechanical complications in metal knee and hip arthroplasty

Background: In contrast to infection or mechanical issues joint replacement failure following inflammatory adverse reactions is poorly understood. Objective: To assess the association of IL-1β polymorphisms and history of allergy with aseptic non-mechanical complications following arthroplasty. Methods: In 102 patients with aseptic non-mechanically caused symptomatic knee or hip arthroplasty (SA) and 93 patients with asymptomatic arthroplasty (AA) questionnaire-based history, patch test with at least standard series, lymphocyte transformation test (LTT) with nickel, cobalt and chromium and interleukin-1 polymorphism analysis were done. Three polymorphisms of the IL1B gene [IL-1b -3954 (rs1143634), IL-1b -511 (rs16944) and IL-1b -31 (rs1143627)] and one polymorphism of the IL1RN gene [IL1RN intron 2, variable number of tandem repeats, VNTR (rs2234663)] were assessed by PCR and gel electrophoresis. Results: We found no significant difference in smoking history and atopy but 25% versus 10% of self-reported metal allergy in SA versus AA; the patch test (respective, LTT) for metal sensitivity was more often positive in SA patients. The allele 498 bp of the IL1RN polymorphism occurred significantly more often in the SA group (37% versus 11%; p < 0.0001). Upon additional presence of atopy, the difference was even greater (60% vs 10%) (p < 0.000001). There was no association of IL-1 polymorphisms with metal allergy. Conclusion: The IL1RN VNTR allele 498 bp was strongly associated with SA. In patients with a history of atopy, presence of the IL1RN VNTR allele 498 bp led to a four-fold higher SA prevalence compared to patients without this allele

Statistical tests for intra-tumour clonal co-occurrence and exclusivity

Tumour progression is an evolutionary process in which different clones evolve over time, leading to intra-tumour heterogeneity. Interactions between clones can affect tumour evolution and hence disease progression and treatment outcome. Intra-tumoural pairs of mutations that are overrepresented in a co-occurring or clonally exclusive fashion over a cohort of patient samples may be suggestive of a synergistic effect between the different clones carrying these mutations. We therefore developed a novel statistical testing framework, called GeneAccord, to identify such gene pairs that are altered in distinct subclones of the same tumour. We analysed our framework for calibration and power. By comparing its performance to baseline methods, we demonstrate that to control type I errors, it is essential to account for the evolutionary dependencies among clones. In applying GeneAccord to the single-cell sequencing of a cohort of 123 acute myeloid leukaemia patients, we find 1 clonally co-occurring and 8 clonally exclusive gene pairs. The clonally exclusive pairs mostly involve genes of the key signalling pathways

A Broadband Study of Galactic Dust Emission

We have combined infrared data with HI, H2 and HII surveys in order to spatially decompose the observed dust emission into components associated with different phases of the gas. An inversion technique is applied. For the decomposition, we use the IRAS 60 and 100 micron bands, the DIRBE 140 and 240 micron bands, as well as Archeops 850 and 2096 micron wavelengths. In addition, we apply the decomposition to all five WMAP bands. We obtain longitude and latitude profiles for each wavelength and for each gas component in carefully selected Galactic radius bins.We also derive emissivity coefficients for dust in atomic, molecular and ionized gas in each of the bins.The HI emissivity appears to decrease with increasing Galactic radius indicating that dust associated with atomic gas is heated by the ambient interstellar radiation field (ISRF). By contrast, we find evidence that dust mixed with molecular clouds is significantly heated by O/B stars still embedded in their progenitor clouds. By assuming a modified black-body with emissivity law lambda^(-1.5), we also derive the radial distribution of temperature for each phase of the gas. All of the WMAP bands except W appear to be dominated by emission from something other than normal dust, most likely a mixture of thermal bremstrahlung from diffuse ionized gas, synchrotron emission and spinning dust. Furthermore, we find indications of an emissivity excess at long wavelengths (lambda > 850 micron) in the outer Galaxy (R > 8.9 kpc). This suggests either the existence of a very cold dust component in the outer Galaxy or a temperature dependence of the spectral emissivity index. Finally, it is shown that ~ 80% of the total FIR luminosity is produced by dust associated with atomic hydrogen, in agreement with earlier findings by Sodroski et al. (1997).Comment: accepted for publication by A&