983 research outputs found
The ATLAS Pixel Detector
The ATLAS Pixel Detector is the innermost layer of the ATLAS tracking system
and will contribute significantly to the ATLAS track and vertex reconstruction.
The detector consists of identical sensor-chip-hybrid modules, arranged in
three barrels in the centre and three disks on either side for the forward
region.
The position of the Pixel Detector near the interaction point requires
excellent radiation hardness, mechanical and thermal robustness, good long-term
stability, all combined with a low material budget. The detector layout,
results from final prototyping and the status of production are presented.Comment: Talk at the VERTEX2003 conference, Lake Windermere, UK, September
2003, 6 pages, LaTeX, 6 eps figure
Diamond Prototypes for the ATLAS SLHC Pixel Detector
Vertex detectors at future hadron colliders will need to cope with large
particle fluences. Diamond is a particularly radiation hard material and
exhibits further properties that makes it an attractive material for such
detectors. Within the RD42 collaboration several chemical vapor deposition
diamond samples are being studied in the form of strip and pixel detectors.
While the quality of the poly-crystalline diamond samples is constantly
increasing and the feasibility of producing wafers has been demonstrated,
recently a single-crystal diamond pixel detector has been assembled and
characterized in a 100 GeV particle beam at CERN. Results on performance,
detection efficiency, spatial resolution and charge collection are reported
here together with the latest radiation damage studies.Comment: 3 pages, 8 figures, 1st International conference on Technology and
Instrumentation in Particle Physics (TIPP09
The expression of phasal polarity in Kambaata (Cushitic)
Paper submitted to "The Expression of Phasal Polarity in African Languages", edited by Raija Krame
DEPFET detectors for direct detection of MeV Dark Matter particles
The existence of dark matter is undisputed, while the nature of it is still
unknown. Explaining dark matter with the existence of a new unobserved particle
is among the most promising possible solutions. Recently dark matter candidates
in the MeV mass region received more and more interest. In comparison to the
mass region between a few GeV to several TeV, this region is experimentally
largely unexplored. We discuss the application of a RNDR DEPFET semiconductor
detector for direct searches for dark matter in the MeV mass region. We present
the working principle of the RNDR DEPFET devices and review the performance
obtained by previously performed prototype measurements. The future potential
of the technology as dark matter detector is discussed and the sensitivity for
MeV dark matter detection with RNDR DEPFET sensors is presented. Under the
assumption of three background events in the region of interest and an exposure
of one kgy a sensitivity of cm
for dark matter particles with a mass of 10 MeV can be reached.Comment: submitted to EPJ
Targeting ALK and WIP1 : neuroblastoma precision medicine under development
Neuroblastoma is the childhood solid tumor accountable for the largest number of deaths, calling for improved treatment. Some genetic alterations are considered crucial in driving initiation and progression of neuroblastoma. These are usually associated with poor prognosis and are viewed as potential therapeutic targets. Anaplastic lymphoma kinase (ALK) is one of the best-established disease drivers in neuroblastoma, harboring oncogenic mutations or amplifications in about 10-15 % of all cases. In 2013, results from the first phase I study of an ALK inhibitor in neuroblastoma, crizotinib, were announced showing disappointing clinical response. Improved later-generation ALK inhibitors have since become available while biological and clinical understanding of ALK mutations in neuroblastoma has increased.
In Paper I, a patient with a metastatic high-risk neuroblastoma suffered extreme toxicity due to an underlying condition, Fanconi anemia, prohibiting further conventional treatment. Whole genome sequencing of tumor material revealed a novel ALK variant, ALK-I1171T, which was identified as a potent gain-of-function mutant resistant to crizotinib, but sensitive to later-generation ALK inhibitors including ceritinib. It was shown that ceritinib was equally effective as crizotinib in a panel of ALK-driven neuroblastoma cell lines. As a result, the child could be offered ceritinib in monotherapy, achieving complete metastatic remission and enabling resection of the primary tumor, and long-term survival.
In Paper II, activation of ALK as well as tropomyosin-related kinase A (TRKA) was observed in the absence of corresponding genomic alterations in an infant with metastasized and treatment-refractory neuroblastoma. A novel germline mutation of the ALK ligand ALKAL-2 was revealed by whole genome sequencing, which in cell culture and drosophila experiments was shown to be functional. Since an inhibitor targeting both ALK and TRKA was available in entrectinib, this drug was tested in neuroblastoma cell lines. Subsequently entrectinib treatment could be offered to the patient, producing a prompt improvement of clinical status and a gradual decline of catecholamine markers and metastases over the course of several years.
The majority of high-risk neuroblastomas contain a gain of chromosome 17q, a feature that correlates with aggressive disease and poor prognosis. The gene PPM1D is situated within the gained region and encodes the phosphatase WIP1, an inhibitor of p53 and a negative regulator of DNA damage response. WIP1 is often overexpressed in neuroblastoma, and overexpression in transgenic mice predisposes to tumor formation. In Paper III we showed that WIP1 expression correlates to 17q gain in neuroblastoma and medulloblastoma cell lines, which are also highly dependent on WIP1. Knockdown of WIP1 delayed tumor growth. Among different small molecule WIP1 inhibitors evaluated, SL-176 was demonstrated to be effective in all tested cell lines regardless of p53 mutational status. Pharmacologic inhibition of WIP1 with SL-176 in xenograft-bearing mice curbed tumor growth.
To achieve an improved cytotoxic effect, a drug combination screening with the WIP1 inhibitor SL-176 was conducted in Paper IV, identifying combination with epigenetic modification by inhibition of the histone demethylase JMJD3 as the most synergistic strategy. Combination of SL-176 and the JMJD3 inhibitor GSK-J4 showed strong synergism in a panel of neuroblastoma cell lines with regard to cell viability, WIP1 downstream targets, cell cycle arrest and apoptosis. Pathway analysis of differentially expressed genes, as identified by RNA sequencing, revealed enrichment of genes involved in pathways associated with DNA damage response.
While ALK inhibitors are already available to a subset of neuroblastoma patients, WIP1 is a promising therapeutic target where much work remains before patients may potentially benefit. It is our conviction that in the future, targeted therapy will be available to all high-risk neuro-blastoma patients. This thesis represents a few small steps on the road to accomplish that goal
The expression of elevation in demonstratives of the Omotic-Lowland East Cushitic contact zone
International audienc
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