345 research outputs found
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
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
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
First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07)
Background: Oral temozolomide has shown similar efficacy to dacarbazine in phase III trials with median progression-free survival (PFS) of 2.1 months. Bevacizumab has an inhibitory effect on the proliferation of melanoma and sprouting endothelial cells. We evaluated the addition of bevacizumab to temozolomide to improve efficacy in stage IV melanoma. Patients and methods: Previously untreated metastatic melanoma patients with Eastern Cooperative Oncology Group performance status of two or more were treated with temozolomide 150 mg/m2 days 1-7 orally and bevacizumab 10 mg/kg body weight i.v. day 1 every 2 weeks until disease progression or unacceptable toxicity. The primary end point was disease stabilisation rate [complete response (CR), partial response (PR) or stable disease (SD)] at week 12 (DSR12); secondary end points were best overall response, PFS, overall survival (OS) and adverse events. Results: Sixty-two patients (median age 59 years) enrolled at nine Swiss centres. DSR12 was 52% (PR: 10 patients and SD: 22 patients). Confirmed overall response rate was 16.1% (CR: 1 patient and PR: 9 patients). Median PFS and OS were 4.2 and 9.6 months. OS (12.0 versus 9.2 months; P = 0.014) was higher in BRAF V600E wild-type patients. Conclusions: The primary end point was surpassed showing promising activity of this bevacizumab/temozolomide combination with a favourable toxicity profile. Response and OS were significantly higher in BRAF wild-type patient
Semi-Dense 3D Reconstruction with a Stereo Event Camera
Event cameras are bio-inspired sensors that offer several advantages, such as
low latency, high-speed and high dynamic range, to tackle challenging scenarios
in computer vision. This paper presents a solution to the problem of 3D
reconstruction from data captured by a stereo event-camera rig moving in a
static scene, such as in the context of stereo Simultaneous Localization and
Mapping. The proposed method consists of the optimization of an energy function
designed to exploit small-baseline spatio-temporal consistency of events
triggered across both stereo image planes. To improve the density of the
reconstruction and to reduce the uncertainty of the estimation, a probabilistic
depth-fusion strategy is also developed. The resulting method has no special
requirements on either the motion of the stereo event-camera rig or on prior
knowledge about the scene. Experiments demonstrate our method can deal with
both texture-rich scenes as well as sparse scenes, outperforming
state-of-the-art stereo methods based on event data image representations.Comment: 19 pages, 8 figures, Video: https://youtu.be/Qrnpj2FD1e
In silico Analysis of Combinatorial microRNA Activity Reveals Target Genes and Pathways Associated with Breast Cancer Metastasis
This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited
Low-molecular-weight cyclin E: the missing link between biology and clinical outcome
Cyclin E, a key mediator of transition during the G(1)/S cellular division phase, is deregulated in a wide variety of human cancers. Our group recently reported that overexpression and generation of low-molecular-weight (LMW) isoforms of cyclin E were associated with poor clinical outcome among breast cancer patients. However, the link between LMW cyclin E biology in mediating a tumorigenic phenotype and clinical outcome is unknown. To address this gap in knowledge, we assessed the role of LMW isoforms in breast cancer cells; we found that these forms of cyclin E induced genomic instability and resistance to p21, p27, and antiestrogens in breast cancer. These findings suggest that high levels of LMW isoforms of cyclin E not only can predict failure to endocrine therapy but also are true prognostic indicators because of their influence on cell proliferation and genetic instability
Cis and Trans Effects of Human Genomic Variants on Gene Expression
This work was funded by the Louis-Jeantet Foundation (http://www.jeantet.ch/), the European Research Council (Grant ID: 260927 http://erc.europa.eu/), the Swiss National Foundation (Grant ID: 130342 http://www.snf.ch), NCCR Frontiers In Genetics (http://www.frontiers-in-genetics.org), the UK Medical Research Council (http://www.mrc.ac.uk) and the Wellcome Trust (Grant ID: 092731).
Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma
International audienceBACKGROUND: The von Hippel-Lindau gene (VHL) alteration, a common event in sporadic clear-cell renal-cell carcinoma (CCRCC), leads to highly vascularised tumours. Vascular endothelial growth factor (VEGF) is the major factor involved in angiogenesis, but the prognostic significance of both VHL inactivation and VEGF expression remain controversial. The aims of this study were to analyse the relationship between VHL genetic and epigenetic alterations, VHL expression and VEGF tumour or plasma expression, and to analyse their respective prognostic value in patients with CCRCC. METHODS: A total of 102 patients with CCRCC were prospectively analysed. Alterations in VHL were determined by sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-specific MLPA. Expression of pVHL and VEGF was determined by immunohistochemistry. Plasma VEGF was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: VHL mutation, deletion and promoter methylation were identified in 70, 76 and 14 cases, respectively. Overall, at least one VHL-gene alteration occurred in 91 cases (89.2%). Both VEGF tumour and plasma expression appeared to be decreased in case of VHL alteration. Median progression-free survival and CCRCC-specific survival were significantly reduced in patients with wild-type VHL or altered VHL and high VEGF expression, which, therefore, represent two markers of tumour aggressiveness in CCRCC. CONCLUSION: Stratifying CCRCCs according to VHL and VEGF status may help tailor therapeutic strategy
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