Using a family history questionnaire to identify adult patients with increased genetic risk for sarcoma.

BACKGROUND: Sarcomas in adults can be associated with hereditary cancer syndromes characterized by early-onset predisposition to numerous types of cancer. Because of variability in familial presentation and the largely unexplained genetic basis of sarcomas, ascertainment of patients for whom a genetics evaluation is most indicated poses challenges. We assessed the utility of a Sarcoma Clinic Genetic Screening (scgs) questionnaire in facilitating that task. METHODS: Between 2008 and 2012, 169 patients (median age: 53 years; range: 17-88 years) completed a self-administered scgs questionnaire. A retrospective chart review was completed for all respondents, and descriptive statistics were reported. Probands were divided into two groups depending on whether they did or did not report a family history of Li-Fraumeni syndrome-type cancers. RESULTS: A family history of cancer (as far as 3rd-degree relatives) was reported in 113 of 163 sarcoma patients (69%). Eeles Li-Fraumeni-like (lfl) criteria were fulfilled in 46 probands (28%), Chompret lfl in 21 (13%), Birch lfl in 8 (5%), and classic Li-Fraumeni in none. In the 10 probands tested for TP53 mutations, 1 pathogenic mutation was found. Further investigation of selected families led to the discovery of germline mutations in MLH1, MSH2, and APC genes in 3 individuals. CONCLUSIONS: The scgs questionnaire was useful for ascertaining probands with sarcoma who could benefit from a genetic assessment. The tool allowed us to identify high-risk families fitting the criteria for lfl and, surprisingly, other hereditary cancer syndromes. Similar questionnaires could be used in other cancer-specific clinics to increase awareness of the genetic component of these cancers.

IOeRT conventional and FLASH treatment planning system implementation exploiting fast GPU Monte Carlo: The case of breast cancer.

Partial breast irradiation for the treatment of early-stage breast cancer patients can be performed by means of Intra Operative electron Radiation Therapy (IOeRT). One of the main limitations of this technique is the absence of a treatment planning system (TPS) that could greatly help in ensuring a proper coverage of the target volume during irradiation. An IOeRT TPS has been developed using a fast Monte Carlo (MC) and an ultrasound imaging system to provide the best irradiation strategy (electron beam energy, applicator position and bevel angle) and to facilitate the optimisation of dose prescription and delivery to the target volume while maximising the organs at risk sparing. The study has been performed in silico, exploiting MC simulations of a breast cancer treatment. Ultrasound-based input has been used to compute the absorbed dose maps in different irradiation strategies and a quantitative comparison between the different options was carried out using Dose Volume Histograms. The system was capable of exploring different beam energies and applicator positions in few minutes, identifying the best strategy with an overall computation time that was found to be completely compatible with clinical implementation. The systematic uncertainty related to tissue deformation during treatment delivery with respect to imaging acquisition was taken into account. The potential and feasibility of a GPU based full MC TPS implementation of IOeRT breast cancer treatments has been demonstrated in-silico. This long awaited tool will greatly improve the treatment safety and efficacy, overcoming the limits identified within the clinical trials carried out so far.

Healthy aging: what can we learn from Caenorhabditis elegans?

The microscopic worm Caenorhabditis elegans (C. elegans) is one of the most prominent animal models for aging studies. This is underscored by the fact that most of the genes and interventions that modulate the aging process, such as the insulin/IGF pathway, caloric restriction and mitochondrial signalling, were first identified in this organism. Remarkably, many features of the mammalian aging process are recapitulated in C. elegans: over time, damage to macromolecule accumulates, structural cellular components progressively deteriorate, physiological functions decline, resistance to stress and infections decreases, while morbidity and mortality rates increase. In humans, age represents risk factor number one for most diseases ultimately leading to death in industrialized countries, namely cardiovascular diseases, cancer and neurodegenerative disorders. Genes regulating aging in C. elegans are evolutionarily conserved and their deregulation is often involved in the development of age-associated diseases in humans. It is therefore likely that any intervention that extends C. elegans lifespan will indicate strategies to positively impact on healthy human longevity.

GPU-accelerated Monte Carlo simulation of electron and photon interactions for radiotherapy applications.

Objective. The Monte Carlo simulation software is a valuable tool in radiation therapy, in particular to achieve the needed accuracy in the dose evaluation for the treatment plans optimisation. The current challenge in this field is the time reduction to open the way to many clinical applications for which the computational time is an issue. In this manuscript we present an innovative GPU-accelerated Monte Carlo software for dose valuation in electron and photon based radiotherapy, developed as an update of the FRED (Fast paRticle thErapy Dose evaluator) software.Approach. The code transports particles through a 3D voxel grid, while scoring their energy deposition along their trajectory. The models of electromagnetic interactions in the energy region between 1 MeV-1 GeV available in literature have been implemented to efficiently run on GPUs, allowing to combine a fast tracking while keeping high accuracy in dose assessment. The FRED software has been bench-marked against state-of-art full MC (FLUKA, GEANT4) in the realm of two different radiotherapy applications: Intra-Operative Radio Therapy and Very High Electron Energy radiotherapy applications.Results. The single pencil beam dose-depth profiles in water as well as the dose map computed on non-homogeneous phantom agree with full-MCs at 2% level, observing a gain in processing time from 200 to 5000.Significance. Such performance allows for computing a plan with electron beams in few minutes with an accuracy of ∼%, demonstrating the FRED potential to be adopted for fast plan re-calculation in photon or electron radiotherapy applications.

Vectorial phase retrieval for linear characterization of attosecond pulses.

The waveforms of attosecond pulses produced by high-harmonic generation carry information on the electronic structure and dynamics in atomic and molecular systems. Current methods for the temporal characterization of such pulses have limited sensitivity and impose significant experimental complexity. We propose a new linear and all-optical method inspired by widely used multidimensional phase retrieval algorithms. Our new scheme is based on the spectral measurement of two attosecond sources and their interference. As an example, we focus on the case of spectral polarization measurements of attosecond pulses, relying on their most fundamental property-being well confined in time. We demonstrate this method numerically by reconstructing the temporal profiles of attosecond pulses generated from aligned CO(2) molecules.

Enhanced propagation for relativistic laser pulses in inhomogeneous plasmas using hollow channels.

The influence of long (several millimeters) and hollow channels, bored in inhomogeneous ionized plasma by using a long pulse laser beam, on the propagation of short, ultraintense laser pulses has been studied. Compared to the case without a channel, propagation in channels significantly improves beam transmission and maintains a beam quality close to propagation in vacuum. In addition, the growth of the forward-Raman instability is strongly reduced. These results are beneficial for the direct scheme of the fast ignitor concept of inertial confinement fusion as we demonstrate, in fast-ignition-relevant conditions, that with such channels laser energy can be carried through increasingly dense plasmas close to the fuel core with minimal losses.

Author Correction: Quantitative phase contrast imaging of a shock-wave with a laser-plasma based X-ray source.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Inter-fractional monitoring of [Formula: see text]C ions treatments: results from a clinical trial at the CNAO facility.

The high dose conformity and healthy tissue sparing achievable in Particle Therapy when using C ions calls for safety factors in treatment planning, to prevent the tumor under-dosage related to the possible occurrence of inter-fractional morphological changes during a treatment. This limitation could be overcome by a range monitor, still missing in clinical routine, capable of providing on-line feedback. The Dose Profiler (DP) is a detector developed within the INnovative Solution for In-beam Dosimetry in hadronthErapy (INSIDE) collaboration for the monitoring of carbon ion treatments at the CNAO facility (Centro Nazionale di Adroterapia Oncologica) exploiting the detection of charged secondary fragments that escape from the patient. The DP capability to detect inter-fractional changes is demonstrated by comparing the obtained fragment emission maps in different fractions of the treatments enrolled in the first ever clinical trial of such a monitoring system, performed at CNAO. The case of a CNAO patient that underwent a significant morphological change is presented in detail, focusing on the implications that can be drawn for the achievable inter-fractional monitoring DP sensitivity in real clinical conditions. The results have been cross-checked against a simulation study.

Regularised patient-specific stopping power calibration for proton therapy planning based on proton radiographic images.

Proton transmission imaging has been proposed and investigated as imaging modality complementary to x-ray based techniques in proton beam therapy. In particular, it addresses the issue of range uncertainties due to the conversion of an x-ray patient computed tomography (CT) image expressed in Hounsfield Units (HU) to relative stopping power (RSP) needed as input to the treatment planning system. One approach to exploit a single proton radiographic projection is to perform a patient-specific calibration of the CT to RSP conversion curve by optimising the match between a measured and a numerically integrated proton radiography. In this work, we develop the mathematical tools needed to perform such an optimisation in an efficient and robust way. Our main focus lies on set-ups which combine pencil beam scanning with a range telescope detector, although most of our methods can be employed in combination with other set-ups as well. Proton radiographies are simulated in Monte Carlo using an idealised detector and applying the same data processing chain used with experimental data. This approach allows us to have a ground truth CT-RSP curve to compare the optimisation results with. Our results show that the parameters of the CT-RSP curve are strongly correlated when using a pencil beam based set-up, which leads to unrealistic variation in the optimised CT-RSP curves. To address this issue, we introduce a regularisation procedure which guarantees a plausible degree of smoothness in the optimised CT-RSP curves. We investigate three different methods to perform the numerical projection operation needed to generate a proton digitally reconstructed radiography. We find that the approximate and computationally faster method performs as well as the more accurate but more demanding method. We perform a Monte Carlo experiment based on a head and neck patient to evaluate the range accuracy achievable with the optimised CT-RSP curves and find an agreement with the ground truth expectation of better than [Formula: see text]. Our results further indicate that the region in the patient in which the proton radiography is acquired does not necessarily have to correspond to the treatment volume to achieve this accuracy. This is important as the imaged region could be freely chosen, e.g. in order to spare organs at risk.

Quantitative phase contrast imaging of a shock-wave with a laser-plasma based X-ray source.

X-ray phase contrast imaging (XPCI) is more sensitive to density variations than X-ray absorption radiography, which is a crucial advantage when imaging weakly-absorbing, low-Z materials, or steep density gradients in matter under extreme conditions. Here, we describe the application of a polychromatic X-ray laser-plasma source (duration ~0.5 ps, photon energy >1 keV) to the study of a laser-driven shock travelling in plastic material. The XPCI technique allows for a clear identification of the shock front as well as of small-scale features present during the interaction. Quantitative analysis of the compressed object is achieved using a density map reconstructed from the experimental data.

Review and performance of the Dose Profiler, a particle therapy treatments online monitor.

Particle therapy (PT) can exploit heavy ions (such as He, C or O) to enhance the treatment efficacy, profiting from the increased Relative Biological Effectiveness and Oxygen Enhancement Ratio of these projectiles with respect to proton beams. To maximise the gain in tumor control probability a precise online monitoring of the dose release is needed, avoiding unnecessary large safety margins surroundings the tumor volume accounting for possible patient mispositioning or morphological changes with respect to the initial CT scan. The Dose Profiler (DP) detector, presented in this manuscript, is a scintillating fibres tracker of charged secondary particles (mainly protons) that will be operating during the treatment, allowing for an online range monitoring. Such monitoring technique is particularly promising in the context of heavy ions PT, in which the precision achievable by other techniques based on secondary photons detection is limited by the environmental background during the beam delivery. Developed and built at the SBAI department of "La Sapienza", within the INSIDE collaboration and as part of a Centro Fermi flagship project, the DP is a tracker detector specifically designed and planned for clinical applications inside a PT treatment room. The DP operation in clinical like conditions has been tested with the proton and carbon ions beams of Trento proton-therapy center and of the CNAO facility. In this contribution the detector performances are presented, in the context of the carbon ions monitoring clinical trial that is about to start at the CNAO centre.

Secondary radiation measurements for particle therapy applications: Charged secondaries produced by 16O ion beams in a PMMA target at large angles.

Particle therapy is a therapy technique that exploits protons or light ions to irradiate tumor targets with high accuracy. Protons and 12C ions are already used for irradiation in clinical routine, while new ions like 4He and 16O are currently being considered. Despite the indisputable physical and biological advantages of such ion beams, the planning of charged particle therapy treatments is challenged by range uncertainties, i.e. the uncertainty on the position of the maximal dose release (Bragg Peak - BP), during the treatment. To ensure correct 'in-treatment' dose deposition, range monitoring techniques, currently missing in light ion treatment techniques, are eagerly needed. The results presented in this manuscript indicate that charged secondary particles, mainly protons, produced by an 16O beam during target irradiation can be considered as candidates for 16O beam range monitoring. Hereafter, we report on the first yield measurements of protons, deuterons and tritons produced in the interaction of an 16O beam impinging on a PMMA target, as a function of detected energy and particle production position. Charged particles were detected at 90° and 60° with respect to incoming beam direction, and homogeneous and heterogeneous PMMA targets were used to probe the sensitivity of the technique to target inhomogeneities. The reported secondary particle yields provide essential information needed to assess the accuracy and resolution achievable in clinical conditions by range monitoring techniques based on secondary charged radiation.

Publisher Correction: Laser-accelerated particle beams for stress testing of materials.

The original version of the Supplementary Information associated with this Article contained an error in Supplementary Figure 3 in which all panels, with the exception of the bottom-left 'Ti' panel, were blank. The HTML has been updated to include a corrected version of the Supplementary Information.

Laser-accelerated particle beams for stress testing of materials.

Laser-driven particle acceleration, obtained by irradiation of a solid target using an ultra-intense (I > 1018 W/cm2) short-pulse (duration <1 ps) laser, is a growing field of interest, in particular for its manifold potential applications in different domains. Here, we provide experimental evidence that laser-generated particles, in particular protons, can be used for stress testing materials and are particularly suited for identifying materials to be used in harsh conditions. We show that these laser-generated protons can produce, in a very short time scale, a strong mechanical and thermal damage, that, given the short irradiation time, does not allow for recovery of the material. We confirm this by analyzing changes in the mechanical, optical, electrical, and morphological properties of five materials of interest to be used in harsh conditions.

Fred: a GPU-accelerated fast-Monte Carlo code for rapid treatment plan recalculation in ion beam therapy.

Ion beam therapy is a rapidly growing technique for tumor radiation therapy. Ions allow for a high dose deposition in the tumor region, while sparing the surrounding healthy tissue. For this reason, the highest possible accuracy in the calculation of dose and its spatial distribution is required in treatment planning. On one hand, commonly used treatment planning software solutions adopt a simplified beam-body interaction model by remapping pre-calculated dose distributions into a 3D water-equivalent representation of the patient morphology. On the other hand, Monte Carlo (MC) simulations, which explicitly take into account all the details in the interaction of particles with human tissues, are considered to be the most reliable tool to address the complexity of mixed field irradiation in a heterogeneous environment. However, full MC calculations are not routinely used in clinical practice because they typically demand substantial computational resources. Therefore MC simulations are usually only used to check treatment plans for a restricted number of difficult cases. The advent of general-purpose programming GPU cards prompted the development of trimmed-down MC-based dose engines which can significantly reduce the time needed to recalculate a treatment plan with respect to standard MC codes in CPU hardware. In this work, we report on the development of fred, a new MC simulation platform for treatment planning in ion beam therapy. The code can transport particles through a 3D voxel grid using a class II MC algorithm. Both primary and secondary particles are tracked and their energy deposition is scored along the trajectory. Effective models for particle-medium interaction have been implemented, balancing accuracy in dose deposition with computational cost. Currently, the most refined module is the transport of proton beams in water: single pencil beam dose-depth distributions obtained with fred agree with those produced by standard MC codes within 1-2% of the Bragg peak in the therapeutic energy range. A comparison with measurements taken at the CNAO treatment center shows that the lateral dose tails are reproduced within 2% in the field size factor test up to 20 cm. The tracing kernel can run on GPU hardware, achieving 10 million primary [Formula: see text] on a single card. This performance allows one to recalculate a proton treatment plan at 1% of the total particles in just a few minutes.

Laser-driven shock waves studied by x-ray radiography.

Multimegabar laser-driven shock waves are unique tools for studying matter under extreme conditions. Accurate characterization of shocked matter is for instance necessary for measurements of equation of state data or opacities. This paper reports experiments performed at the LULI facility on the diagnosis of shock waves, using x-ray-absorption radiography. Radiographs are analyzed using standard Abel inversion. In addition, synthetic radiographs, which also take into account the finite size of the x-ray source, are generated using density maps produced by hydrodynamic simulations. Reported data refer to both plane cylindrical targets and hemispherical targets. Evolution and deformation of the shock front could be followed using hydrodynamic simulations.

The effect of a calcium carbonate/perlite toothpaste on the removal of extrinsic tooth stain in two weeks.

OBJECTIVE: To assess the effect of a calcium carbonate/perlite toothpaste on the levels of extrinsic stain removed at two weeks compared to a silica control toothpaste. DESIGN: In this parallel group, double-blind study, subjects were stratified by natural baseline stain and tobacco use and allocated at random to one of the two study toothpastes. Subjects brushed with their allocated toothpaste twice daily for two weeks before extrinsic tooth stain was again assessed. SETTING: The study was performed at 4-Front Research UK Limited, Maldon, UK. PARTICIPANTS: 152 adult subjects with at least eight assessable incisors/ canines with natural extrinsic tooth stain completed the study. METHODS: The extrinsic tooth stain on the facial surfaces of incisors and canines was measured using the Macpherson modification of the Lobene Stain Index. RESULTS: Both of the toothpaste groups had significantly less stain after two weeks of use compared to the baseline value (p<0.001). Analysis of covariance on the sum of the whole mouth stain scores showed that the calcium carbonate/perlite toothpaste removed significantly more stain over the two week study than the silica control toothpaste (p<0.05). CONCLUSIONS: Twice daily brushing for two weeks with a calcium carbonate/perlite toothpaste removes more extrinsic stain than a silica control toothpaste.

Clinical, biochemical, and molecular investigations of a genetic isolate of growth hormone insensitivity (Laron's syndrome).

We have characterized the GH receptor mutation that is responsible for extreme short stature and GH insensitivity in a Bahamian genetic isolate. Heights of affected individuals ranged from -4.0 to -6.3 SD. Like others with Laron's syndrome, they had normal to high serum GH concentrations and low serum insulin-like growth factor I concentrations. Circulating levels of GH-binding protein activity were below limits of detection. Amplification of exons 2-7 and screening with single strand conformational polymorphism analysis located an abnormality in exon 7. Sequencing identified homozygosity for a C to T transition in the third position of codon 236. Reverse transcription and PCR amplification of complementary DNA from lymphocytes showed that this same sense mutation generated a new splice donor site 63 bp 5' to the normal exon 7 splice site. This novel site was used to the exclusion of the normal site in homozygotes. Both normal and variant messenger ribonucleic acid species were detected in heterozygotes. The predicted protein lacks 21 amino acids, including those defining the WS-like motif of the GH receptor extracellular domain. The high frequency of Laron's syndrome in this isolated island population probably reflects the introduction of the G236 splice mutation by a settler early in the 300-yr history of English settlement.

Connexin43 mRNA contains a functional internal ribosome entry site.

A reporter gene construct was used to study the regulation of connexin43 (Cx43) expression, the major gap junction protein found in heart and uterus, in transfected cell lines. The construct had the firefly luciferase gene under the control of the Cx43 promoter. Inclusion of the 5'-untranslated region (UTR) of the mRNA in the construct increased luciferase expression by 70%. A bicistronic vector assay demonstrated that the Cx43 5'-UTR contains a strong internal ribosome entry site (IRES). Deletion analysis localized the IRES element to the upstream portion of the 5'-UTR.

Environmental and urinary reference values as markers of exposure to hydrocarbons in urban areas.

A study using individual dosimetry to evaluate the daily inhaled dose of sixteen aromatic and aliphatic hydrocarbons in three groups of primary school children, living in three Italian towns with 50,000 inhabitants or less, (Treviglio-Lombardy; Poggibonsi-Tuscany; Valenza-Piedmont) is presented. The simultaneous use of two passive samplers (radial diffusion) for each child, for a 24 h period, determined both the indoor and indoor + outdoor environmental reference concentrations. We measured the urinary levels of benzene, toluene, ethylbenzene and xylenes for each child and hence determined the urinary reference values for BTEX. We also considered the possibility of using benzene in urine as a biomarker of environmental exposure of the general population to this xenobiotic. We evaluated how both the environmental and biological measures were influenced by the presence of smokers in the surveyed children's houses. For the group of children living in Poggibonsi, we considered the influence of the living area and the traffic density on environmental concentrations of benzene (indoor and indoor + outdoor).