Ein Ansatz zur anwenderorientierten Systemmodellierung für die interdisziplinäre Produktentwicklung = A User-Oriented Concept of Systems Modeling for Interdisciplinary Product Engineering

Die Welt verändert sich, auch für den Menschen in der Produktentwicklung. War früher die Kompetenz eines Entwicklers durch disziplinspezifisches Fachwissen geprägt, ist heute und in Zukunft eine interdisziplinäre Ausrichtung des Kompetenzprofils erforderlich. Die Karlsruher Schule der Produktentwicklung begreift diesen Menschen als denkendes und handelndes Zentrum in der Produktentstehung

Time Resolution Studies with Timepix3 Assemblies with Thin Silicon Pixel Sensors

Timepix3 is a multi-purpose readout ASIC for hybrid pixel detectors. It can measure time and energy simultaneously by employing time-of-arrival (ToA) and time-over-threshold (ToT) techniques. Both methods are systematically affected by timewalk. In this paper, a method for pixel-by-pixel calibration of the time response is presented. Assemblies of Timepix3 ASICs bump-bonded to thin planar silicon pixel sensors of different thicknesses between 50 um and 150 um are calibrated and characterised in particle beams. For minimum ionising particles, time resolutions down to 0.72 $\pm$ 0.04 ns are achieved.Comment: preprint submitted to JINST, revision

First Direct Observation of Collider Neutrinos with FASER at the LHC

We report the first direct observation of neutrino interactions at a particle collider experiment. Neutrino candidate events are identified in a 13.6 TeV center-of-mass energy $pp$ collision data set of 35.4 fb${}^{-1}$ using the active electronic components of the FASER detector at the Large Hadron Collider. The candidates are required to have a track propagating through the entire length of the FASER detector and be consistent with a muon neutrino charged-current interaction. We infer $153^{+12}_{-13}$ neutrino interactions with a significance of 16 standard deviations above the background-only hypothesis. These events are consistent with the characteristics expected from neutrino interactions in terms of secondary particle production and spatial distribution, and they imply the observation of both neutrinos and anti-neutrinos with an incident neutrino energy of significantly above 200 GeV.Comment: Submitted to PRL on March 24 202

The FASER Detector

FASER, the ForwArd Search ExpeRiment, is an experiment dedicated to searching for light, extremely weakly-interacting particles at CERN's Large Hadron Collider (LHC). Such particles may be produced in the very forward direction of the LHC's high-energy collisions and then decay to visible particles inside the FASER detector, which is placed 480 m downstream of the ATLAS interaction point, aligned with the beam collisions axis. FASER also includes a sub-detector, FASER$\nu$, designed to detect neutrinos produced in the LHC collisions and to study their properties. In this paper, each component of the FASER detector is described in detail, as well as the installation of the experiment system and its commissioning using cosmic-rays collected in September 2021 and during the LHC pilot beam test carried out in October 2021. FASER will start taking LHC collision data in 2022, and will run throughout LHC Run 3

Stable W and Mo isotopic evidence for increasing redox-potentials from the Paleoarchean towards the Paleoproterozoic deep ocean

The scavenging of dissolved trace metals such as chromium (Cr), molybdenum (Mo) and tungsten (W) and their authigenic enrichment in sedimentary archives mainly occur by particle shuttling that cause resolvable isotope fractionation. Because their scavenging is also dependent on the local marine redox potential and the overall marine chemical environment, the stable isotope composition of these elements in Archean sediments is widely used as paleoredox proxy. Tungsten, a new element in this tool box, is dissolved as the oxyanion tungstate (WO42-) at extremely low marine redox potentials and can thus help to reconstruct the earliest changes in the marine redox state. We tested the applicability of stable W isotopes as a new paleoredox proxy of the atmosphere-ocean system. We analyzed the delta W-186/184 of Precambrian igneous rocks to investigate the detrital background delta W-186/184 signature. This Precambrian igneous inventory (PII) shows delta W-186/184 values between -0.007 and +0.097%o, identical to the range of modern igneous crustal rocks, which indicates that the average Earth's crust delta W-186/184 remained constant over billions of years. Furthermore, we present delta W-186/184 values of euxinic sediments from the Black Sea as a modern sedimentary analog, which we then compare with delta W-186/184 data of Archean and Proterozoic black shales (3.47-2.3 Ga). Modern Black Sea sapropels reveal crustal-like delta W-186/184 values between +0.050 and +0.071%o suggesting limited authigenic enrichment of W in euxinic environments. Similarly, post-Great Oxidation Event shales (2.3 Ga) show crustal- or PII-like delta W-186/184 values indicating the deposition in euxinic or oxic environment. However, the Archean shale sample suites show elevated W concentrations and fractionated delta W-186/184 values up to +0.246%o, which we attribute to authigenic enrichment of heavy seawater W in a ferruginous setting. Thus, black shales delta W-186/184 values can help to distinguish between anoxic-ferruginous and euxinic depositional environments. Furthermore, we combine previously published Cr and Mo isotope data with new Cr and W isotope data to quantify the evolution of the marine redox state during the Archean. By combining the Eh-pH stability fields of W and Mo with the delta W-186/184 and delta Mo-98/95 values of Precambrian sediments, we suggest a 3-step evolution of the Precambrian ocean. (1) From 3.47 to 3.0 Ga, the Eh of a dominantly ferruginous ocean was between -0.4 V and -0.25 V, enabling the persistence of soluble WO42- but not MoO42- and thus only the authigenic enrichment of isotopically fractionated W. (2) Starting from 3.0 Ga, the Eh of some shallow-marine environments increased above -0.25 V, as indicated by delta Mo-98/95 values above the detrital background in shallow-marine sediments, while the Eh of the deep ocean still remained below -0.25 V indicated by the lack of authigenic Mo enrichment and fractionated delta Mo-98/95 values in deep-sea shales. (3) After 2.7 Ga elevated delta Mo-98/95 and delta W-186/184 values in deep-marine sediments suggest that the Eh of the ferruginous open-ocean now also increased above -0.25 V. We therefore suggest that the combination of delta Mo-98/95 and delta W-186/184 values of shales is a very promising tool to investigate earliest changes in marine redox conditions during the Archean. (C) 2021 Elsevier Ltd. All rights reserved

Corryvreckan: A Modular 4D Track Reconstruction and Analysis Software for Test Beam Data

Corryvreckan is a versatile, highly configurable software with a modular structure designed to reconstruct and analyse test beam and laboratory data. It caters to the needs of the test beam community by providing a flexible offline event building facility to combine detectors with different read-out schemes, with or without trigger information, and includes the possibility to correlate data from multiple devices based on timestamps. Hit timing information, available with high precision from an increasing number of detectors, can be used in clustering and tracking to reduce combinatorics. Several algorithms, including an implementation of Millepede-II, are provided for offline alignment. A graphical user interface enables direct monitoring of the reconstruction progress and can be employed for quasi-online monitoring during data taking. This work introduces the Corryvreckan framework architecture and user interface, and provides a detailed overview of the event building algorithm. The reconstruction and analysis capabilities are demonstrated with data recorded at the DESY II Test Beam Facility using the EUDAQ2 data acquisition framework with an EUDET-type beam telescope, a Timepix3 timing reference, a fine-pitch planar silicon sensor with CLICpix2 readout and the AIDA Trigger Logic Unit. The individual steps of the reconstruction chain are presented in detail

Corryvreckan: A Modular 4D Track Reconstruction and Analysis Software for Test Beam Data

Corryvreckan is a versatile, highly configurable software with a modular structure designed to reconstruct and analyse test beam and laboratory data. It caters to the needs of the test beam community by providing a flexible offline event building facility to combine detectors with different read-out schemes, with or without trigger information, and includes the possibility to correlate data from multiple devices based on timestamps. Hit timing information, available with high precision from an increasing number of detectors, can be used in clustering and tracking to reduce combinatorics. Several algorithms, including an implementation of Millepede-II, are provided for offline alignment. A graphical user interface enables direct monitoring of the reconstruction progress and can be employed for quasi-online monitoring during data taking. This work introduces the Corryvreckan framework architecture and user interface, and provides a detailed overview of the event building algorithm. The reconstruction and ana- lysis capabilities are demonstrated with data recorded at the DESY II Test Beam Facility using the EUDAQ2 data acquisition framework with an EUDET-type beam telescope, a Timepix3 timing reference, a fine-pitch planar silicon sensor with CLICpix2 readout and the AIDA Trigger Logic Unit. The individual steps of the reconstruction chain are presented in detail.Corryvreckan is a versatile, highly configurable software with a modular structure designed to reconstruct and analyse test beam and laboratory data. It caters to the needs of the test beam community by providing a flexible offline event building facility to combine detectors with different read-out schemes, with or without trigger information, and includes the possibility to correlate data from multiple devices based on timestamps. Hit timing information, available with high precision from an increasing number of detectors, can be used in clustering and tracking to reduce combinatorics. Several algorithms, including an implementation of Millepede-II, are provided for offline alignment. A graphical user interface enables direct monitoring of the reconstruction progress and can be employed for quasi-online monitoring during data taking. This work introduces the Corryvreckan framework architecture and user interface, and provides a detailed overview of the event building algorithm. The reconstruction and analysis capabilities are demonstrated with data recorded at the DESY II Test Beam Facility using the EUDAQ2 data acquisition framework with an EUDET-type beam telescope, a Timepix3 timing reference, a fine-pitch planar silicon sensor with CLICpix2 readout and the AIDA Trigger Logic Unit. The individual steps of the reconstruction chain are presented in detail.Corryvreckan is a versatile, highly configurable software with a modular structure designed to reconstruct and analyse test beam and laboratory data. It caters to the needs of the test beam community by providing a flexible offline event building facility to combine detectors with different readout schemes, with or without trigger information, and includes the possibility to correlate data from multiple devices based on timestamps. Hit timing information, available with high precision from an increasing number of detectors, can be used in clustering and tracking to reduce combinatorics. Several algorithms, including an implementation of Millepede-II, are provided for offline alignment. A graphical user interface enables direct monitoring of the reconstruction progress and can be employed for quasi-online monitoring during data taking. This work introduces the Corryvreckan framework architecture and user interface, and provides a detailed overview of the event building algorithm. The reconstruction and analysis capabilities are demonstrated with data recorded at the DESY II Test Beam Facility using the EUDAQ2 data acquisition framework with an EUDET-type beam telescope, a Timepix3 timing reference, a fine-pitch planar silicon sensor with CLICpix2 readout and the AIDA Trigger Logic Unit. The individual steps of the reconstruction chain are presented in detail

Time and Energy Calibration of Timepix3 Assemblies with Thin Silicon Sensors

The Timepix3 ASIC is a multi-purpose readout chip for hybrid pixel detectors. It can measure time and energy simultaneously by employing time-of-arrival (ToA) and time-over-threshold (ToT) techniques. In the presented work, a time efficient method for pixel-by-pixel calibration of both ToA and ToT is investigated. Five assemblies of Timepix3 ASICs bump bonded to silicon pixel sensors of different thicknesses between 50 μm and 150 μm are calibrated with electrical test pulses, x-ray fluorescence and beams of minimum ionising particles in a reference telescope. After calibration, the energy resolution at 6.40 keV is 9.3 %. For 120 GeV/c pions, time resolutions down to 0.72 ns are achieved

Ipilimumab and nivolumab in advanced hepatocellular carcinoma after failure of prior immune checkpoint inhibitor-based combination therapies: a multicenter retrospective study

Introduction Immune checkpoint inhibitor (ICI)-based regimens are transforming the landscape of hepatocellular carcinoma (HCC) treatment. We describe the effect of combined ipilimumab and nivolumab in patients with advanced HCC after the failure of prior ICI-based combination treatments. Methods The clinical course of patients with advanced HCC who received combined ipilimumab and nivolumab after prior ICI-based combination therapies was assessed. Progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) per RECIST v1.1 and mRECIST, overall survival (OS), and safety were analyzed. Results Of 109 patients treated with atezolizumab and bevacizumab or other ICI-based combination treatments, ten patients received subsequent therapy with ipilimumab and nivolumab. The majority of patients had Barcelona Clinic Liver Cancer (BCLC) Stage C (80%) HCC and a preserved liver function as defined by Child-Pugh A (80%). At a median follow-up of 15.3 months, ORR for ipilimumab and nivolumab was 30% with a DCR of 40%. Median PFS was 2.9 months and the median OS was 7.4 months. Conclusion This retrospective study demonstrates that combined ipilimumab and nivolumab can be effective and tolerable after prior ICI-based combination therapies and provides a rationale for the prospective clinical evaluation of this treatment sequencing

TRAIL receptor targeting agents potentiate PARP inhibitor efficacy in pancreatic cancer independently of BRCA2 mutation status

Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists