620 research outputs found
Critical Review of Norovirus Surrogates in Food Safety Research: Rationale for Considering Volunteer Studies
The inability to propagate human norovirus (NoV) or to clearly differentiate infectious from noninfectious virus particles has led to the use of surrogate viruses, like feline calicivirus (FCV) and murine norovirus-1 (MNV), which are propagatable in cell culture. The use of surrogates is predicated on the assumption that they generally mimic the viruses they represent; however, studies are proving this concept invalid. In direct comparisons between FCV and MNV, their susceptibility to temperatures, environmental and food processing conditions, and disinfectants are dramatically different. Differences have also been noted between the inactivation of NoV and its surrogates, thus questioning the validity of surrogates. Considerable research funding is provided globally each year to conduct surrogate studies on NoVs; however, there is little demonstrated benefit derived from these studies in regard to the development of virus inactivation techniques or food processing strategies. Human challenge studies are needed to determine which processing techniques are effective in reducing NoVs in foods. A major obstacle to clinical trials on NoVs is the perception that such trials are too costly and risky, but in reality, there is far more cost and risk in allowing millions of unsuspecting consumers to contract NoV illness each year, when practical interventions are only a few volunteer studies away. A number of clinical trials have been conducted, providing important insights into NoV inactivation. A shift in research priorities from surrogate research to volunteer studies is essential if we are to identify realistic, practical, and scientifically valid processing approaches to improve food safety
Expression and Function of Ccbe1 in the Chick Early Cardiogenic Regions Are Required for Correct Heart Development
During the course of a differential screen to identify transcripts specific for chick heart/hemangioblast precursor cells, we have identified Ccbe1 (Collagen and calcium-binding EGF-like domain 1). While the importance of Ccbe1 for the development of the lymphatic system is now well demonstrated, its role in cardiac formation remained unknown. Here we show by whole-mount in situ hybridization analysis that cCcbe1 mRNA is initially detected in early cardiac progenitors of the two bilateral cardiogenic fields (HH4), and at later stages on the second heart field (HH9-18). Furthermore, cCcbe1 is expressed in multipotent and highly proliferative cardiac progenitors. We characterized the role of cCcbe1 during early cardiogenesis by performing functional studies. Upon morpholino-induced cCcbe1 knockdown, the chick embryos displayed heart malformations, which include aberrant fusion of the heart fields, leading to incomplete terminal differentiation of the cardiomyocytes. cCcbe1 overexpression also resulted in severe heart defects, including cardia bifida. Altogether, our data demonstrate that although cardiac progenitors cells are specified in cCcbe1 morphants, the migration and proliferation of cardiac precursors cells are impaired, suggesting that cCcbe1 is a key gene during early heart development.FCT [SFRH/BD/65628/2009, SFRH/BPD/86497/2012, SFRH/BPD/41081/2007]; F.C.T.B.I. fellowship [PTDC/SAU-BID/114902/ 2009]; FCT; Institute for Biotechnology Bioengineering (Centro Biomedicina Molecular e Celular (IBB/CBME), Laboratorio Associado (LA) in the frame of Project [PestOE/EQB/LA0023/2013]info:eu-repo/semantics/publishedVersio
Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study)
Background: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). Subjects, Materials, and Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. Results: Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. Conclusion: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. Implications for Practice: PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months
Design and Simulated Performance of Calorimetry Systems for the ECCE Detector at the Electron Ion Collider
We describe the design and performance the calorimeter systems used in the
ECCE detector design to achieve the overall performance specifications
cost-effectively with careful consideration of appropriate technical and
schedule risks. The calorimeter systems consist of three electromagnetic
calorimeters, covering the combined pseudorapdity range from -3.7 to 3.8 and
two hadronic calorimeters. Key calorimeter performances which include energy
and position resolutions, reconstruction efficiency, and particle
identification will be presented.Comment: 19 pages, 22 figures, 5 table
AI-assisted Optimization of the ECCE Tracking System at the Electron Ion Collider
The Electron-Ion Collider (EIC) is a cutting-edge accelerator facility that
will study the nature of the "glue" that binds the building blocks of the
visible matter in the universe. The proposed experiment will be realized at
Brookhaven National Laboratory in approximately 10 years from now, with
detector design and R&D currently ongoing. Notably, EIC is one of the first
large-scale facilities to leverage Artificial Intelligence (AI) already
starting from the design and R&D phases. The EIC Comprehensive Chromodynamics
Experiment (ECCE) is a consortium that proposed a detector design based on a
1.5T solenoid. The EIC detector proposal review concluded that the ECCE design
will serve as the reference design for an EIC detector. Herein we describe a
comprehensive optimization of the ECCE tracker using AI. The work required a
complex parametrization of the simulated detector system. Our approach dealt
with an optimization problem in a multidimensional design space driven by
multiple objectives that encode the detector performance, while satisfying
several mechanical constraints. We describe our strategy and show results
obtained for the ECCE tracking system. The AI-assisted design is agnostic to
the simulation framework and can be extended to other sub-detectors or to a
system of sub-detectors to further optimize the performance of the EIC
detector.Comment: 16 pages, 18 figures, 2 appendices, 3 table
ECCE Sensitivity Studies for Single Hadron Transverse Single Spin Asymmetry Measurements
We performed feasibility studies for various single transverse spin
measurements that are related to the Sivers effect, transversity and the tensor
charge, and the Collins fragmentation function. The processes studied include
semi-inclusive deep inelastic scattering (SIDIS) where single hadrons (pions
and kaons) were detected in addition to the scattered DIS lepton. The data were
obtained in {\sc pythia}6 and {\sc geant}4 simulated e+p collisions at 18 GeV
on 275 GeV, 18 on 100, 10 on 100, and 5 on 41 that use the ECCE detector
configuration. Typical DIS kinematics were selected, most notably
GeV, and cover the range from to . The single spin
asymmetries were extracted as a function of and , as well as the
semi-inclusive variables , and . They are obtained in azimuthal moments
in combinations of the azimuthal angles of the hadron transverse momentum and
transverse spin of the nucleon relative to the lepton scattering plane. The
initially unpolarized MonteCarlo was re-weighted in the true kinematic
variables, hadron types and parton flavors based on global fits of fixed target
SIDIS experiments and annihilation data. The expected statistical
precision of such measurements is extrapolated to 10 fb and potential
systematic uncertainties are approximated given the deviations between true and
reconstructed yields. The impact on the knowledge of the Sivers functions,
transversity and tensor charges, and the Collins function has then been
evaluated in the same phenomenological extractions as in the Yellow Report. The
impact is found to be comparable to that obtained with the parameterized Yellow
Report detector and shows that the ECCE detector configuration can fulfill the
physics goals on these quantities.Comment: 22 pages, 22 figures, to be submitted to joint ECCE proposal NIM-A
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Open Heavy Flavor Studies for the ECCE Detector at the Electron Ion Collider
The ECCE detector has been recommended as the selected reference detector for
the future Electron-Ion Collider (EIC). A series of simulation studies have
been carried out to validate the physics feasibility of the ECCE detector. In
this paper, detailed studies of heavy flavor hadron and jet reconstruction and
physics projections with the ECCE detector performance and different magnet
options will be presented. The ECCE detector has enabled precise EIC heavy
flavor hadron and jet measurements with a broad kinematic coverage. These
proposed heavy flavor measurements will help systematically study the
hadronization process in vacuum and nuclear medium especially in the
underexplored kinematic region.Comment: Open heavy flavor studies with the EIC reference detector design by
the ECCE consortium. 11 pages, 11 figures, to be submitted to the Nuclear
Instruments and Methods
ECCE unpolarized TMD measurements
We performed feasibility studies for various measurements that are related to
unpolarized TMD distribution and fragmentation functions. The processes studied
include semi-inclusive Deep inelastic scattering (SIDIS) where single hadrons
(pions and kaons) were detected in addition to the scattered DIS lepton. The
single hadron cross sections and multiplicities were extracted as a function of
the DIS variables and , as well as the semi-inclusive variables ,
which corresponds to the momentum fraction the detected hadron carries relative
to the struck parton and , which corresponds to the transverse momentum of
the detected hadron relative to the virtual photon. The expected statistical
precision of such measurements is extrapolated to accumulated luminosities of
10 fb and potential systematic uncertainties are approximated given the
deviations between true and reconstructed yields.Comment: 12 pages, 9 figures, to be submitted in joint ECCE proposal NIM-A
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Anti-angiogenic therapy for cancer: Current progress, unresolved questions and future directions
Tumours require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. Since one or more of the VEGF ligand family is overexpressed in most solid cancers, there was great optimism that inhibition of the VEGF pathway would represent an effective anti-angiogenic therapy for most tumour types. Encouragingly, VEGF pathway targeted drugs such as bevacizumab, sunitinib and aflibercept have shown activity in certain settings. However, inhibition of VEGF signalling is not effective in all cancers, prompting the need to further understand how the vasculature can be effectively targeted in tumours. Here we present a succinct review of the progress with VEGF-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages (metastatic, adjuvant, neoadjuvant), interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness. In terms of future directions, we discuss the need to delineate further the complexities of tumour vascularisation if we are to develop more effective and personalised anti-angiogenic therapies. © 2014 The Author(s)
Measurement of the non-prompt D-meson fraction as a function of multiplicity in proton-proton collisions at = 13 TeV
The fractions of non-prompt (i.e. originating from beauty-hadron decays) D0
and D+ mesons with respect to the inclusive yield are measured as a function of the
charged-particle multiplicity in proton-proton collisions at a centre-of-mass energy of √s =
13 TeV with the ALICE detector at the LHC. The results are reported in intervals of
transverse momentum (pT) and integrated in the range 1 < pT < 24 GeV/c. The fraction
of non-prompt D0 and D+ mesons is found to increase slightly as a function of pT in
all the measured multiplicity intervals, while no significant dependence on the charged-
particle multiplicity is observed. In order to investigate the production and hadronisation
mechanisms of charm and beauty quarks, the results are compared to PYTHIA 8 as well
as EPOS 3 and EPOS 4 Monte Carlo simulations, and to calculations based on the colour
glass condensate including three-pomeron fusion
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