•Ocean color algorithms for obtaining marine inherent optical properties are reviewed.•Known uncertainties associated with each approach and knowledge gaps are discussed.•Common performance metrics ...used to evaluate the satellite retrievals are provided.•Recommendations for future investment for upcoming satellite missions are presented.
Ocean color measured from satellites provides daily global, synoptic views of spectral water-leaving reflectances that can be used to generate estimates of marine inherent optical properties (IOPs). These reflectances, namely the ratio of spectral upwelled radiances to spectral downwelled irradiances, describe the light exiting a water mass that defines its color. IOPs are the spectral absorption and scattering characteristics of ocean water and its dissolved and particulate constituents. Because of their dependence on the concentration and composition of marine constituents, IOPs can be used to describe the contents of the upper ocean mixed layer. This information is critical to further our scientific understanding of biogeochemical oceanic processes, such as organic carbon production and export, phytoplankton dynamics, and responses to climatic disturbances. Given their importance, the international ocean color community has invested significant effort in improving the quality of satellite-derived IOP products, both regionally and globally. Recognizing the current influx of data products into the community and the need to improve current algorithms in anticipation of new satellite instruments (e.g., the global, hyperspectral spectroradiometer of the NASA Plankton, Aerosol, Cloud, ocean Ecosystem (PACE) mission), we present a synopsis of the current state of the art in the retrieval of these core optical properties. Contemporary approaches for obtaining IOPs from satellite ocean color are reviewed and, for clarity, separated based their inversion methodology or the type of IOPs sought. Summaries of known uncertainties associated with each approach are provided, as well as common performance metrics used to evaluate them. We discuss current knowledge gaps and make recommendations for future investment for upcoming missions whose instrument characteristics diverge sufficiently from heritage and existing sensors to warrant reassessing current approaches.
Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) ...subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in
(87%) and
(73%), amplification of
(47%), and homozygous deletion of
(40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase
and the pancreatic cancer stem cell regulator
in all three ASCPs, and a
fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the
fusion-positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer. SIGNIFICANCE: These data provide a unique description of the ASCP genomic and epigenomic landscape and identify candidate therapeutic targets for this dismal cancer.
FLUKA is a general purpose Monte Carlo code able to describe the transport and interaction of any particle and nucleus type in complex geometries over an energy range extending from thermal neutrons ...to ultrarelativistic hadron collisions. It has many different applications in accelerator design, detector studies, dosimetry, radiation protection, medical physics, and space research. In 2019, CERN and INFN, as FLUKA copyright holders, together decided to end their formal collaboration framework, allowing them henceforth to pursue different pathways aimed at meeting the evolving requirements of the FLUKA user community, and at ensuring the long term sustainability of the code. To this end, CERN set up the FLUKA.CERN Collaboration
1
. This paper illustrates the physics processes that have been newly released or are currently implemented in the code distributed by the FLUKA.CERN Collaboration
2
under new licensing conditions that are meant to further facilitate access to the code, as well as intercomparisons. The description of coherent effects experienced by high energy hadron beams in crystal devices, relevant to promising beam manipulation techniques, and the charged particle tracking in vacuum regions subject to an electric field, overcoming a former lack, have already been made available to the users. Other features, namely the different kinds of low energy deuteron interactions as well as the synchrotron radiation emission in the course of charged particle transport in vacuum regions subject to magnetic fields, are currently undergoing systematic testing and benchmarking prior to release. FLUKA is widely used to evaluate radiobiological effects, with the powerful support of the Flair graphical interface, whose new generation (Available at
http://flair.cern
) offers now additional capabilities, e.g., advanced 3D visualization with photorealistic rendering and support for industry-standard volume visualization of medical phantoms. FLUKA has also been playing an extensive role in the characterization of radiation environments in which electronics operate. In parallel, it has been used to evaluate the response of electronics to a variety of conditions not included in radiation testing guidelines and standards for space and accelerators, and not accessible through conventional ground level testing. Instructive results have been obtained from Single Event Effects (SEE) simulations and benchmarks, when possible, for various radiation types and energies. The code has reached a high level of maturity, from which the FLUKA.CERN Collaboration is planning a substantial evolution of its present architecture. Moving towards a modern programming language allows to overcome fundamental constraints that limited development options. Our long term goal, in addition to improving and extending its physics performances with even more rigorous scientific oversight, is to modernize its structure to integrate independent contributions more easily and to formalize quality assurance through state-of-the-art software deployment techniques. This includes a continuous integration pipeline to automatically validate the codebase as well as automatic processing and analysis of a tailored physics-case test suite. With regard to the aforementioned objectives, several paths are currently envisaged, like finding synergies with Geant4, both at the core structure and interface level, this way offering the user the possibility to run with the same input different Monte Carlo codes and crosscheck the results.
Key events in T cell-dependent antibody responses, including affinity maturation, are dependent on the B cell's presentation of antigen to helper T cells at critical checkpoints in germinal-center ...formation in secondary lymphoid organs. Here we found that signaling via Toll-like receptor 9 (TLR9) blocked the ability of antigen-specific B cells to capture, process and present antigen and to activate antigen-specific helper T cells in vitro. In a mouse model in vivo and in a human clinical trial, the TLR9 agonist CpG enhanced the magnitude of the antibody response to a protein vaccine but failed to promote affinity maturation. Thus, TLR9 signaling might enhance antibody titers at the expense of the ability of B cells to engage in germinal-center events that are highly dependent on B cells' capture and presentation of antigen.
The Large Hadron Collider (LHC) will be upgraded in 2019/2020 to increase its luminosity (rate of collisions) by a factor of five beyond its design value and the integrated luminosity by a factor ...ten, in order to maintain scientific progress and exploit its full capacity. The novel machine configuration, called High Luminosity LHC (HL-LHC), will increase consequently the level of activation of its components. The evaluation of the radiological impact of the HL-LHC operation in the Long Straight Sections of the Insertion Region 1 (ATLAS) and Insertion Region 5 (CMS) is presented. Using the Monte Carlo code FLUKA, ambient dose equivalent rate estimations have been performed on the basis of two announced operating scenarios and using the latest available machine layout. The HL-LHC project requires new technical infrastructure with caverns and 300 m long tunnels along the Insertion Regions 1 and 5. The new underground service galleries will be accessible during the operation of the accelerator machine. The radiological risk assessment for the Civil Engineering work foreseen to start excavating the new galleries in the next LHC Long Shutdown and the radiological impact of the machine operation will be discussed.
Amplification of chromosome 9p24.1 targeting PD-L1, PD-L2, and JAK2 (PDJ amplicon) is present in subsets of triple negative breast cancers (TNBCs) and is associated with poor clinical outcomes. ...However, the prevalence of PDJ+ TNBCs varies extensively across studies applying different methods for interrogating samples of interest. To rigorously assess the prevalence of PDJ amplicons in TNBC, its prognostic value and whether it is enriched by chemotherapy, we interrogated 360 TNBC samples including 74 surgical resections from patients treated in the neoadjuvant setting, and tissue microarrays (TMAs) with 31 cases from African American women and 255 resected non-metastatic cases, with a 3 color fluorescence in situ hybridization (FISH) assay targeting the 9p24.1 PDJ amplicon, 9q24.3, and 9q34.1. Samples with mean PDJ signal of > 4.5 copies, and ratios of PDJ/9q24 ≥ 2 and/or PDJ/9q34.1 ≥ 2 were called amplified (PDJ+). Correlative analyses included the association of tumor infiltrating lymphocytes (TILs) with PDJ amplicons in TNBCs. In addition, we investigated intratumor copy number of PDJ amplicons in PDJ+ and PDJ- TNBCs. Matched pre- and post-neoadjuvant treatment biopsies were available from patients (n = 6) to evaluate the effects of therapy on PDJ status. Our study provides a rigorous analysis of the prevalence, distribution, and clinical correlatives of the PDJ amplicon in TNBC.
Smac mimetic promotes apoptosis by neutralizing inhibitor of apoptosis (IAP) proteins and is considered as a promising cancer therapeutic. Although an autocrine/paracrine tumor necrosis factor-α ...(TNFα) loop has been implicated in Smac mimetic-induced cell death, little is yet known about additional factors that determine sensitivity to Smac mimetic. Using genome-wide gene expression analysis, we identify death receptor 5 (DR5) as a novel key mediator of Smac mimetic-induced apoptosis. Although several cell lines that are sensitive to the Smac mimetic BV6 die in a TNFα-dependent manner, A172 glioblastoma cells undergo BV6-induced apoptosis largely independently of TNFα/TNFR1, as the TNFα-blocking antibody Enbrel or TNFR1 knockdown provide little protection. Yet, BV6-stimulated nuclear factor-κB (NF-κB) activation is critically required for apoptosis, as inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor (IκBα-SR) blocks BV6-induced apoptosis. Unbiased genome-wide gene expression studies in IκBα-SR-overexpressing cells versus vector control cells reveal that BV6 increases DR5 expression in a NF-κB-dependent manner. Importantly, this BV6-stimulated upregulation of DR5 is critically required for apoptosis, as transient or stable knockdown of DR5 significantly inhibits BV6-triggered apoptosis. In addition, DR5 silencing attenuates formation of a RIP1/FADD/caspase-8 cytosolic cell death complex and activation of caspase-8, -3 and -9. By identifying DR5 as a critical mediator of Smac mimetic-induced apoptosis, our findings provide novel insights into the determinants that control susceptibility of cancer cells to Smac mimetic.
The CERN High-Energy AcceleRator Mixed field (CHARM) facility provides a secondary particle field, produced by irradiating a thick target with 24 GeV/c protons supplied by the proton synchrotron. In ...order to investigate the thermalization process of secondary neutrons in the CHARM facility, we measured the thermal neutrons using the gold foil activation method. Bare and Cd-covered gold foils were placed at 35 positions to deduce the thermal neutron distribution in the CHARM facility. The 197Au(n, γ)198Au reaction rates and thermal neutron fluxes measured in this study were compared with the Monte Carlo simulation codes, PHITS, FLUKA, and MARS. The comparison between the measured and simulated values gives an agreement better than a factor of two. Besides, we investigated the simple empirical formula to estimate a thermal neutron flux in the accelerator room, ϕth = CQ/S, where Q is the neutron source intensity and S is the total surface area of a room. The coefficient C estimated in this study did not significantly depend on the incident proton beam energy.
The CERN High Energy AcceleRator Mixed field facility (CHARM) is located in the CERN Proton Synchrotron (PS) East Experimental Area. The facility receives a pulsed proton beam from the CERN PS with a ...beam momentum of 24 GeV/c with 5⋅1011 protons per pulse with a pulse length of 350 ms and with a maximum average beam intensity of 6.7⋅1010p/s that then impacts on the CHARM target.
The shielding of the CHARM facility also includes the CERN Shielding Benchmark Facility (CSBF) situated laterally above the target. This facility consists of 80 cm of cast iron and 360 cm of concrete with barite concrete in some places.
Activation samples of bismuth and aluminium were placed in the CSBF and in the CHARM access corridor in July 2015. Monte Carlo simulations with the FLUKA code have been performed to estimate the specific production yields for these samples. The results estimated by FLUKA Monte Carlo simulations are compared to activation measurements of these samples.
The comparison between FLUKA simulations and the measured values from γ-spectrometry gives an agreement better than a factor of 2.
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