Treatment of evolving cancers will require dynamic decision support.

Cancer research has traditionally focused on developing new agents, but an underexplored question is that of the dose and frequency of existing drugs. Based on the modus operandi established in the early days of chemotherapies, most drugs are administered according to predetermined schedules that seek to deliver the maximum tolerated dose and are only adjusted for toxicity. However, we believe that the complex, evolving nature of cancer requires a more dynamic and personalized approach. Chronicling the milestones of the field, we show that the impact of schedule choice crucially depends on processes driving treatment response and failure. As such, cancer heterogeneity and evolution dictate that a one-size-fits-all solution is unlikely-instead, each patient should be mapped to the strategy that best matches their current disease characteristics and treatment objectives (i.e. their 'tumorscape'). To achieve this level of personalization, we need mathematical modeling. In this perspective, we propose a five-step 'Adaptive Dosing Adjusted for Personalized Tumorscapes (ADAPT)' paradigm to integrate data and understanding across scales and derive dynamic and personalized schedules. We conclude with promising examples of model-guided schedule personalization and a call to action to address key outstanding challenges surrounding data collection, model development, and integration.

New perspectives for neutron imaging through advanced event-mode data acquisition.

Imaging using scintillators is a widespread and cost-effective approach in radiography. While different types of scintillator and sensor configurations exist, it can be stated that the detection efficiency and resolution of a scintillator-based system strongly depend on the scintillator material and its thickness. Recently developed event-driven detectors are capable of registering spots of light emitted by the scintillator after a particle interaction, allowing to reconstruct the Center-of-Mass of the interaction within the scintillator. This results in a more precise location of the event and therefore provides a pathway to overcome the scintillator thickness limitation and increase the effective spatial resolution of the system. Utilizing this principle, we present a detector capable of Time-of-Flight imaging with an adjustable field-of-view, ad-hoc binning and re-binning of data based on the requirements of the experiment including the possibility of particle discrimination via the analysis of the event shape in space and time. It is considered that this novel concept might replace regular cameras in neutron imaging detectors as it provides superior detection capabilities with the most recent results providing an increase by a factor 3 in image resolution and an increase by up to a factor of 7.5 in signal-to-noise for thermal neutron imaging.

3D sub-pixel correlation length imaging.

Quantitative 2D neutron dark-field-imaging with neutron grating interferometry has been used to characterize structures in the size range below the imaging resolution. We present the first 3D quantitative neutron dark-field imaging experiment. We characterize sub-pixel structure sizes below the imaging resolution in tomography by quantitatively analyzing the change in dark-field contrast with varying neutron wavelength. This proof of principle experiment uses a dedicated reference sample with four different solutions of microspheres, each with a different diameter. The result is a 3D tomogram featuring a real space scattering function in each voxel. The presented experiment is expected to mark the path for future material science research through the individual quantification of small-angle scattering structures in each voxel of a volume of a bulk inhomogeneous sample material.

Achromatic Non-Interferometric Single Grating Neutron Dark-Field Imaging.

We demonstrate a simple single grating beam modulation technique, which enables the use of a highly intense neutron beam for differential phase and dark-field contrast imaging and thus spatially resolved structural correlation measurements in full analogy to interferometric methods. In contrast to these interferometric approaches our method is intrinsically achromatic and provides unprecedented flexibility in the choice of experimental parameters. In particular the method enables straight forward application of quantitative dark-field contrast imaging in time-of-flight mode at pulsed neutron sources. Utilizing merely a macroscopic absorption mask unparalleled length scales become accessible. We present results of quantitative dark-field contrast imaging combining microstructural small angle scattering analyses with real space imaging for a variety of materials.

Visualizing the heterogeneous breakdown of a fractal microstructure during compaction by neutron dark-field imaging.

Structural properties of cohesive powders are dominated by their microstructural composition. Powders with a fractal microstructure show particularly interesting properties during compaction where a microstructural transition and a fractal breakdown happen before compaction and force transport. The study of this phenomenon has been challenging due to its long-range effect and the subsequent necessity to characterize these microstructural changes on a macroscopic scale. For the detailed investigation of the complex nature of powder compaction for various densification states along with the heterogeneous breakdown of the fractal microstructure we applied neutron dark-field imaging in combination with a variety of supporting techniques with various spatial resolutions, field-of-views and information depths. We used scanning electron microscopy to image the surface microstructure in a small field-of-view and X-ray tomography to image density variations in 3D with lower spatial resolution. Non-local spin-echo small-angle neutron scattering results are used to evaluate fitting models later used as input parameters for the neutron dark-field imaging data analysis. Finally, neutron dark-field imaging results in combination with supporting measurements using scanning electron microscopy, X-ray tomography and spin-echo small angle scattering allowed us to comprehensively study the heterogeneous transition from a fractal to a homogeneous microstructure of a cohesive powder in a quantitative manner.

A Monte Carlo approach for scattering correction towards quantitative neutron imaging of polycrystals.

The development of neutron imaging from a qualitative inspection tool towards a quantitative technique in materials science has increased the requirements for accuracy significantly. Quantifying the thickness or the density of polycrystalline samples with high accuracy using neutron imaging has two main problems: (i) the scattering from the sample creates artefacts on the image and (ii) there is a lack of specific reference attenuation coefficients. This work presents experimental and simulation results to explain and approach these problems. Firstly, a series of neutron radiography and tomography experiments of iron, copper and vanadium are performed and serve as a reference. These materials were selected because they attenuate neutrons mainly through coherent (Fe and Cu) and incoherent (V) scattering. Secondly, an ad hoc Monte Carlo model was developed, based on beamline, sample and detector parameters, in order to simulate experiments, understand the physics involved and interpret the experimental data. The model, developed in the McStas framework, uses a priori information about the sample geometry and crystalline structure, as well as beamline settings, such as spectrum, geometry and detector type. The validity of the simulations is then verified with experimental results for the two problems that motivated this work: (i) the scattering distribution in transmission imaging and (ii) the calculated attenuation coefficients.

Unlocking high spatial resolution in neutron imaging through an add-on fibre optics taper.

The demand for high resolution neutron imaging has been steadily increasing over the past years. The number of facilities offering cutting edge resolution is however limited, due to (i) the design complexity of an optimized device able to reach a resolution in the order of ≈ 10 µm and (ii) limitations in available neutron flux. Here we propose a simple addition, based on a Fibre Optics Taper (FOT), that can be easily attached to an already existing scintillator-camera imaging detector in order to efficiently increase its spatial resolution and hence boost the capability of an instrument into high resolution applications.

Statistical uncertainty in the dark-field and transmission signal of grating interferometry.

We present a framework to estimate the fundamental statistical uncertainty of grating interferometer experiments based on a Monte-Carlo method. Using the framework, we are able to determine the uncertainty of individual measurements as well as suggesting experimental protocols that minimise the statistical uncertainty for given overall exposure times. The method presented here is valid for both X-rays and neutrons and can be generalised for any modulation measurement.

BioRef II-Neutron reflectometry with relaxed resolution for fast, kinetic measurements at HZB.

We present an upgrade to the time-of-flight neutron reflectometer BioRef at the research reactor BER II of the Helmholtz-Zentrum Berlin für Materialien und Energie (HZB). Through the integration of an additional chopper into the existing setup, the available wavelength resolution is significantly extended. Now two distinct operation modes can be used: a high resolution mode with Δλ/λ ranging from 1% to 5%, which allows for the investigation of thick films up to 4000 Å, and a high flux mode with Δλ/λ = 7%-11%. In the high flux mode, reflectivity curves from 0.007 Å-1 to 0.2 Å-1 with three angular settings can be recorded in 7 min. For a single angular setting and its respective window in Q-space, a time resolution of even less than 4 min is reached. The different configurations are documented by respective measurements (a) on a Ni-Ti multilayer and (b) the swelling kinetics of a solid-supported phospholipid coating upon incubation in a polyelectrolyte solution.

Neutron guide optimisation for a time-of-flight neutron imaging instrument at the European Spallation Source.

A neutron transport system for the planned imaging instrument ODIN at the future European Spallation Source (ESS) based on neutron optical components was designed and optimized. Different ways of prompt pulse suppression were studied. The spectral performance of the optimal neutron guide configuration is presented. In addition, the influence of the gaps in the guide system needed for the required chopper configuration was investigated. Given that the requirements for an imaging instrument located on a long guide system and hosting a complex chopper system are extremely demanding in terms of spectral and divergence needs, this study can be beneficial for a wide range of instruments in various ways.

Quantification of the sensitivity range in neutron dark-field imaging.

In neutron grating interferometry, the dark-field image visualizes the scattering properties of samples in the small-angle and ultra-small-angle scattering range. These angles correspond to correlation lengths from several hundred nanometers up to several tens of micrometers. In this article, we present an experimental study that demonstrates the potential of quantitative neutron dark-field imaging. The dark-field signal for scattering from different particle sizes and concentrations of mono-dispersive polystyrene particles in aqueous solution is compared to theoretical predictions and the good agreement between measurements and calculations underlines the quantitative nature of the measured values and reliability of the technique with neutrons.

The contribution of glutathione to the destabilizing effect of yeast on wheat dough.

Any factor which impairs the development of the gluten network affects the gas retention capacity and the overall baking performance. This study aimed to examine why rising yeast concentrations (Saccharomyces cerevisiae) decrease the dough elasticity in an asymptotic manner. Since in 27 commercial fresh and dry yeasts up to 81 mg glutathione (GSH) per 1g dry sample were found. Through the addition of reduced GSH in dough without yeast, the extent of dough weakening was analysed. Indeed rheological measurements confirmed that yeast-equivalent levels of GSH had a softening effect and during 3h fermentation the weakening coefficient increased from 0.3% to 20.4% in a Rheofermentometer. The present results indicate that free -SH compounds, as represented by GSH, considerably contribute to the softening of dough through dead yeast cells.

General solution for quantitative dark-field contrast imaging with grating interferometers.

Grating interferometer based imaging with X-rays and neutrons has proven to hold huge potential for applications in key research fields conveying biology and medicine as well as engineering and magnetism, respectively. The thereby amenable dark-field imaging modality implied the promise to access structural information beyond reach of direct spatial resolution. However, only here a yet missing approach is reported that finally allows exploiting this outstanding potential for non-destructive materials characterizations. It enables to obtain quantitative structural small angle scattering information combined with up to 3-dimensional spatial image resolution even at lab based x-ray or at neutron sources. The implied two orders of magnitude efficiency gain as compared to currently available techniques in this regime paves the way for unprecedented structural investigations of complex sample systems of interest for material science in a vast range of fields.

Small angle neutron scattering on an absolute intensity scale and the internal surface of diatom frustules from three species of differing morphologies.

The internal nanostructure of the diatoms Cyclotella meneghiniana, Seminavis robusta and Achnanthes subsessilis was investigated using small angle neutron scattering (SANS) to examine thin biosilica samples, consisting of isotropic (powder) from their isolated cell walls. The interpretation of SANS data was assisted by several other measurements. The N2 adsorption, interpreted within the Branuer-Emmet-Teller isotherm, yielded the specific surface area of the material. Fourier transform infrared (FTIR) and Raman spectroscopy indicates that the isolated material is amorphous silica with small amounts of organic cell wall materials acting as a filling material between the silica particles. A two-phase (air and amorphous silica) model was used to interpret small angle neutron scattering data. After correction for instrumental resolution, the measurements on two SANS instruments covered an extended range of scattering vectors 0.0011 nm(-1) < q < 5.6 nm(-1), giving an almost continuous SANS curve over a range of scattering vectors, q, on an absolute scale of intensity for each sample. Each of the samples gave a characteristic scattering curve where log (intensity) versus log (q) has a -4 dependence, with other features superimposed. In the high-q regime, departure from this behaviour was observed at a length-scales equivalent to the proposed unitary silica particle. The limiting Porod scattering law was used to determine the specific area per unit of volume of each sample illuminated by the neutron beam. The Porod behaviour, and divergence from this behaviour, is discussed in terms of various structural features and the proposed mechanisms for the bio-assembly of unitary silica particles in frustules.

Impact of a model synovial fluid on supported lipid membranes.

The interaction of a model synovial fluid, here a solution of 3mg/mL hyaluronic acid (HA) in heavy water (D(2)O), with an oligolamellar stack of lipid (DMPC) membranes on silicon support has been studied by neutron reflectometry and infrared spectroscopy on the molecular scale at non-physiological and physiological conditions. The system under investigation represents a simple model for lipid-coated mammalian joints and other artificial implant surfaces. When exposed to pure D(2)O at 21°C, i.e. below the main phase transition of the system, the lipid membranes show a lamellar spacing of 65Å. Heating to 26°C results in detachment of all lipid bilayers except for the innermost lipid lamella directly adsorbed to the surface of the silicon support. On the contrary, when incubated in the solution of HA in D(2)O the oligolamellar lipid system starts swelling. In addition, heating to 39°C does not result in loss of the lipid membranes into the liquid phase. The interfacial lipid coating adopts a new stable lamellar state with an increase in d-spacing by 380% to 247Å measured after 43 days of incubation with the model synovial fluid. Potential consequences for joint lubrication and protective wear functionality are considered.

BioRef: a versatile time-of-flight reflectometer for soft matter applications at Helmholtz-Zentrum Berlin.

BioRef is a versatile novel time-of-flight reflectometer featuring a sample environment for in situ infrared spectroscopy at the reactor neutron source BER II of the Helmholtz Zentrum Berlin für Materialien und Energie (HZB). After two years of design and construction phase the instrument has recently undergone commissioning and is now available for specular and off-specular neutron reflectivity measurements. BioRef is especially dedicated to the investigation of soft matter systems and studies at the solid-liquid interface. Due to flexible resolution modes and variable addressable wavelength bands that allow for focusing onto a selected scattering vector range, BioRef enables a broad range of surface and interface investigations and even kinetic studies with subsecond time resolution. The instrumental settings can be tailored to the specific requirements of a wide range of applications. The performance is demonstrated by several reference measurements, and the unique option of in situ on-board infrared spectroscopy is illustrated by the example of a phase transition study in a lipid multilayer film.

Three-dimensional imaging of magnetic domains.

Magnetic domains have been the subject of much scientific investigation since their theoretical existence was first postulated by P.-E. Weiss over a century ago. Up to now, the three-dimensional (3D) domain structure of bulk magnets has never been observed owing to the lack of appropriate experimental methods. Domain analysis in bulk matter thus remains one of the most challenging tasks in research on magnetic materials. All current domain observation methods are limited to studying surface domains or thin magnetic films. As the properties of magnetic materials are strongly affected by their domain structure, the development of a technique capable of investigating the shape, size and distribution of individual domains in three dimensions is of great importance. Here, we show that the novel technique of Talbot-Lau neutron tomography with inverted geometry enables direct imaging of the 3D network of magnetic domains within the bulk of FeSi crystals.

Long-term outcome of patients with argininosuccinate lyase deficiency diagnosed by newborn screening in Austria.

Twenty-three patients with late onset argininosuccinate lyase deficiency (ASLD) were identified during a 27-year period of newborn screening in Austria (1:95,600, 95% CI=1:68,036-1:162,531). One additional patient was identified outside the newborn screening with neonatal hyperammonemia. Long-term outcome data were available in 17 patients (median age 13 years) ascertained by newborn screening. Patients were treated with protein restricted diet and oral arginine supplementation during infancy and childhood. IQ was average/above average in 11 (65%), low average in 5 (29%), and in the mild intellectual disability range in 1 (6%) patients. Four patients had an abnormal EEG without evidence of clinical seizures and three had abnormal liver function tests and/or evidence of hepatic steatosis. Plasma citrulline levels were elevated in four patients. Plasma ammonia levels were within normal range prior and after a protein load in all patients. Seven different mutations were identified in the 16 alleles investigated. Four mutations were novel (p.E189G, p.R168C, p.R126P, and p.D423H). All mutations were associated with low argininosuccinate lyase activities (0-15%) in red blood cells. Newborn screening might be beneficial in the prevention of chronic neurologic and intellectual sequelae in late onset ASLD, but a proportion of benign variants might have contributed to the overall favorable outcome as well.

Treatment of chronic allograft nephropathy at late stages using everolimus or FTY720 in combination with cyclosporine.

OBJECTIVE: In this study, we used combined treatment with cyclosporine (CsA)/everolimus (EVR) or CsA/FTY720 to affect ongoing chronic allograft nephropathy (CAN) compared with monotherapy with EVR or FTY720. BACKGROUND: CAN is an important cause of renal allograft loss. Immunosuppressive therapy is based on calcineurin inhibitors, which are associated with nephrotoxicity and decreasing graft function. Thus, alternative treatment regimens, including new immunosuppressants, such as EVR or FTY720, are of interest. We asked whether the combination of CsA with EVR or FTY720 ameliorated the development of CAN more effectively than monotherapy with EVR and/or FTY720 during the later stages of CAN. METHODS: Kidneys from Fisher rats were orthotopically transplanted into Lewis rats. Animals received CsA (1.5 mg/kg/d) for the first 10 days after transplantation. Animals were assigned to 6 groups: EVR (0.5 mg/kg/d), FTY720 (0.5 mg/kg/d), CsA (1.5 mg/kg/d), CsA+EVR (1.5 + 0.5 mg/kg/d), CsA+FTY720 (1.5 + 0.5 mg/kg/d), and vehicle (VEH). Treatment started at week 20. The observation period ended after 28 weeks. RESULTS: Treatment with EVR and FTY720 reduced proteinuria and glomerulosclerosis, suppressed lymphocyte and macrophage infiltration, and resulted in a greater number of apoptotic tubular and interstitial cells compared with the combined treatment groups and controls. CONCLUSION: Although EVR and FTY720 monotherapy delayed the progression of CAN, their combination with CsA had no beneficial effect.

Neutron dark-field tomography.

We report how a grating interferometer yields neutron dark-field scatter images for tomographic investigations. The image contrast is based on ultrasmall-angle scattering. It provides otherwise inaccessible spatially resolved information about the distribution of micrometer and submicrometer sized structural formations. Three complementary sets of tomographic data corresponding to attenuation, differential phase, and small-angle scattering can be obtained from one measurement. The method is compatible with conventional imaging and provides significantly higher efficiency than existing techniques.