Search

Calibration of satellite observations is crucial for ensuring the quality of retrieved products essential for meteorological and climate applications. Calibration is obtained and monitored through a cascade of stages, including postlaunch vicarious calibration/validation activities through comparison with independent reference measurements. Here, the vicarious calibration method using radiative transfer simulations based on reference radiosondes is considered in the framework of the calibration/validation activities for the Microwave Imager (MWI) and the Ice Cloud Imager (ICI) to be launched with the Second Generation of the EUMETSAT Polar System. This paper presents an overview of the uncertainty characterizing the vicarious calibration of MWI and ICI using radiosondes as performed within the EUMETSAT-funded VICIRS study. The uncertainty characterization is pursued following a metrological approach, providing a preliminary estimation of all the identified sources. The same approach is used to develop a rigorous method for estimating the number of comparison pairs (i.e., observations vs. simulations) needed to reach a certain level of accuracy in bias determination.

IMPORTANCE: Checkpoint inhibition in cancer immunotherapy related to T-cell–driven mechanisms of action associated with acute macular neuroretinopathy (AMN) and diffuse retinal venulitis, an adverse event not previously described, is reported here. OBJECTIVE: To describe 2 patients who developed ophthalmologic events after treatment with the programmed death 1 axis inhibitor, atezolizumab. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of 2 patients treated with atezolizumab for metastatic breast cancer and colon cancer, respectively, who presented with AMN and diffuse retinal venulitis conducted at 2 tertiary medical centers. MAIN OUTCOMES AND MEASURES: Multimodal imaging including near infrared, optical coherence tomography, and fluorescein angiography were used to characterize retinal vascular abnormalities. RESULTS: Based on optical coherence tomography and multimodal imaging findings, the clinical diagnosis of AMN associated with diffuse retinal venulitis was made in these 2 patients receiving atezolizumab. CONCLUSIONS AND RELEVANCE: While only 2 cases of patients receiving the programmed death ligand 1 inhibitor atezolizumab who experienced AMN and diffuse retinal venulitis are described here, these findings suggest that patients receiving programmed death 1 axis inhibitor therapies may need to be monitored for unexpected immune-related ocular toxicity including abnormalities of the microvasculature and large retinal vessels. Further studies might investigate the potential mechanisms of retinal vascular changes associated with these therapies.

IMPORTANCE: Atezolizumab (anti–programmed cell death ligand 1 [PD-L1]) is well tolerated and clinically active in multiple cancer types. Its safety and clinical activity in metastatic triple-negative breast cancer (mTNBC) has not been reported. OBJECTIVE: To evaluate the safety, clinical activity, and biomarkers associated with the use of single-agent atezolizumab in patients with mTNBC. DESIGN, SETTING, AND PARTICIPANTS: Women with mTNBC (defined by investigator assessment) were enrolled between January 2013 and February 2016 in a multicohort open-label, phase 1 study at US and European academic medical centers. Median follow-up was 25.3 months (range, 0.4-45.6 months). Eligible patients regardless of line of therapy had measurable disease by Response Evaluation Criteria in Solid Tumors, version 1.1; Eastern Cooperative Oncology Group performance status of 0 to 1; and a representative tumor sample for assessment of immune cell (IC) PD-L1 expression. INTERVENTIONS: Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects or loss of clinical benefit. MAIN OUTCOMES AND MEASURES: Primary outcome was safety and tolerability. Activity and exploratory outcomes included objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Outcomes were assessed in all patients and in key patient subgroups. RESULTS: Among 116 evaluable patients (median age, 53 years [range, 29-82 years]), treatment-related adverse events occurred in 73 (63%); 58 (79%) were grade 1 to 2. Most adverse events occurred within the first treatment year. The ORRs were numerically higher in first-line (5 of 21 [24%]) than in second-line or greater patients (6 of 94 [6%]). Median duration of response was 21 months (range, 3 to ≥38 months). Median PFS was 1.4 (95% CI, 1.3-1.6) months by RECIST and 1.9 (95% CI, 1.4-2.5) months by irRC. In first-line patients, median OS was 17.6 months (95% CI, 10.2 months to not estimable). Patients with PD-L1 expression of at least 1% tumor-infiltrating ICs had higher ORRs and longer OS (12% [11 of 91]; 10.1 [95% CI, 7.0-13.8] months, respectively) than those with less than 1% ICs (0 of 21; 6.0 [95% CI, 2.6-12.6] months, respectively). High levels of ICs (>10%) were independently associated with higher ORRs and longer OS. CONCLUSIONS AND RELEVANCE: Single-agent atezolizumab was well tolerated and provided durable clinical benefit in patients with mTNBC with stable or responding disease and in earlier lines of treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01375842

IMPORTANCE: Atezolizumab (anti–programmed death ligand 1) has demonstrated safety and activity in advanced and metastatic urothelial carcinoma, but its long-term clinical profile remains unknown. OBJECTIVE: To report long-term clinical outcomes with atezolizumab therapy for patients with metastatic urothelial carcinoma. DESIGN, SETTING, AND PARTICIPANTS: Patients were enrolled in an expansion cohort of an ongoing, open-label, phase 1 study. Median follow-up was 37.8 months (range, >0.7 to 44.4 months). Enrollment occurred between March 2013 and August 2015 at US and European academic medical centers. Eligible patients had measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Eastern Cooperative Oncology Group performance status 0 to 1, and a representative tumor sample. Programmed death ligand 1 expression on immune cells was assessed (VENTANA SP142 assay). INTERVENTIONS: Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects, protocol nonadherence, or loss of clinical benefit. MAIN OUTCOMES AND MEASURES: Primary outcome was safety. Secondary outcomes included objective response rate, duration of response, and progression-free survival. Response and overall survival were assessed in key baseline subgroups. RESULTS: Ninety-five patients were evaluable (72 [76%] male; median age, 66 years [range, 36-89 years]). Forty-five (47%) received atezolizumab as third-line therapy or greater. Nine patients (9%) had a grade 3 to 4 treatment-related adverse event, mostly within the first treatment year; no serious related adverse events were observed thereafter. One patient (1%) discontinued treatment due to a related event. No treatment-related deaths occurred. Responses occurred in 26% (95% CI, 18%-36%) of patients. Median duration of response was 22.1 months (range, 2.8 to >41.0 months), and median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months). Median overall survival was 10.1 months (95% CI, 7.3-17.0 months); 3-year OS rate was 27% (95% CI, 17%-36%). Response occurred in 40% (95% CI, 26%-55%; n = 40) and 11% (95% CI, 4%-25%; n = 44) of patients with programmed death ligand 1 expression of at least 5% tumor-infiltrating immune cells (IC2/3) or less than 5% (IC0/1), respectively. Median overall survival in patients with IC2/3 and IC0/1 was 14.6 months (95% CI, 9.0 months to not estimable) and 7.6 months (95% CI, 4.7 to 13.9 months), respectively. CONCLUSIONS AND RELEVANCE: Atezolizumab remained well tolerated and provided durable clinical benefit to a heavily pretreated metastatic urothelial carcinoma population in this long-term study. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01375842

Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8+cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients.

Observational records are more often than not influenced by residual non‐climatic factors which must be detected and adjusted for prior to their usage. In this work, we present a novel approach, named Radiosounding HARMonization (RHARM), providing a homogenized data set of temperature, humidity and wind profiles along with an estimation of the measurement uncertainties for 697 radiosounding stations globally. The RHARM method has been used to adjust twice daily (0000 and 1200 UTC) radiosonde data holdings at 16 pressure levels in the range 1,000–10 hPa, from 1978 to present, provided by the Integrated Global Radiosonde Archive. Relative humidity (RH) data are limited to 250 hPa. The applied adjustments are interpolated to all reported levels. RHARM is the first data set to provide homogenized time series with an estimation of the observational uncertainty at each sounding pressure level. By construction, RHARM adjusted fields are not affected by cross‐contamination of biases across stations and are fully independent of reanalysis data. Analysis of trends for temperature, RH and winds highlights increased geographical coherency of trends over 1978–2000 globally, but especially in the Northern Hemisphere and South America. RHARM shows warming trends of 0.39 K/decade at 300 hPa in the Northern Hemisphere and of 0.25 K/decade in the tropics. The RHARM adjustments also reduce differences with the European Centre for Medium‐Range Weather Forecast ERA5 reanalysis, with the strongest effect in the Northern Hemisphere for temperature and relative humidity. For wind speed, the comparison indicates a good agreement with ERA5 in the troposphere. Systematic observations of atmospheric parameters by balloon soundings have been collected regularly across the globe since decades. However, changes in the instrumentation, calculation algorithms, station re‐locations and other factors can influence the measurement time series, making the identification of climate signals difficult. The availability of measurement metadata, cross‐comparison with (sparser) reference networks and the application of statistical methods allows to greatly improve the physical consistency of the records. We developed the Radiosounding HARMonization (RHARM) methodology to provide users with homogenized radiosonde profiles of temperature, humidity, and wind, along with measurement uncertainties, for 697 locations globally and twice daily based on the Integrated Global Radiosonde Archive. Key features of RHARM are the provision of multiple fundamental atmospheric parameters, adjusted for spurious biases and the inclusion of measurement uncertainties estimated following the standards of the metrological community when available metadata permits. The current version of the RHARM data set can be used to investigate tropospheric weather and climate for the last four decades. The Radiosounding HARMonization (RHARM) data set provides homogenized time series of temperature, relative humidity and wind profiles for hundreds of radiosonde stationsMetrologically accurate estimates of the observational uncertainty are provided together with each observation and variableFor all variables, RHARM increases the geographical coherency of estimated trends and the agreement with a modern atmospheric reanalysis The Radiosounding HARMonization (RHARM) data set provides homogenized time series of temperature, relative humidity and wind profiles for hundreds of radiosonde stations Metrologically accurate estimates of the observational uncertainty are provided together with each observation and variable For all variables, RHARM increases the geographical coherency of estimated trends and the agreement with a modern atmospheric reanalysis

Abstract Many and important integrable Hamiltonian systems are ‘superintegrable’, in the sense that there is an open subset of their 2d-dimensional phase space in which all motions are linear on tori of dimension n

Directional Quasi-Convexity (DQC) is a sufficient condition for Nekhoroshev stability, that is, stability for finite but very long times, of elliptic equilibria of Hamiltonian systems. The numerical detection of DQC is elementary for system with three degrees of freedom. In this article, we propose a recursive algorithm to test DQC in any number n≥4 of degrees of freedom.

The Riemann ellipsoids are steady motions of an ideal, incompressible, self-gravitating fluid that retain an ellipsoidal shape. The existence, properties, and stability of these steady motions have been investigated since Newton's time. Most of the stability results are due to Riemann, who studied Lyapunov stability, and to Chandrasekhar, who studied (primarily numerically) spectral stability, thus obtaining Lyapunov instability results. This article addresses the “Nekhoroshev stability” (stability for finite, but very long time scales) of those Riemann ellipsoids that are spectrally stable but of unknown Lyapunov stability. We base our analysis on a Hamiltonian formulation of the problem derived from Riemann's original formulation (which we interpret here as a formulation on a covering space) using recent results from Hamiltonian perturbation theory. Given the complexity of the system, we resort to numerical calculations at certain steps of the stability analysis. As a prerequisite to our analysis, we repeat the Lyapunov and spectral stability analyses, finding important discrepancies with Chandrasekhar's findings. We provide numerical evidence that (i) There are spectrally stable ellipsoids of type II and the region of spectral stability of the ellipsoids of type III is significantly larger than that found by Chandrasekhar. The regions of spectral stability of the ellipsoids of types I, II and III have a finer and subtler structure than was previously believed. (ii) All Riemann ellipsoids, except a finite number of codimension-one resonant subfamilies, are Nekhoroshev-stable.

We recently described a novel way to isolate populations of antigen-reactive CD4+ T cells with a wide range of reactivity to a specific antigen, using immunization with a fixed dose of nominal antigen and FACS® sorting by CD4high expression. Phenotypic, FACS®, functional, antibody inhibition, and major histocompatibility complex–peptide tetramer analyses, as well as T cell receptor Vβ sequence analyses, of the antigen-specific CD4high T cell populations demonstrated that a diverse sperm whale myoglobin 110–121–reactive CD4+ T cell repertoire was activated at the beginning (day 3 after immunization) of the immune response. Within 6 d of immunization, lower affinity clones were lost from the responding population, leaving an expanded population of oligoclonal, intermediate affinity (and residual high affinity) T cells. This T cell subset persisted for at least 4 wk after immunization and dominated the secondary immune response. These data provide evidence that CD4+ T cell repertoire selection occurs early in the immune response in vivo and suggest that persistence and expansion of a population of oligoclonal, intermediate affinity T cells is involved in CD4+ T cell memory.

The future installation of the Large Hadron Collider (LHC) in the tunnel presently housing the Large Electron Positron collider (LEP) requires the dismantling of the latter after more than 10 years of operation. The decommissioning of an accelerator facility leads to the production of large amounts of waste, which in the case of an electron accelerator mostly is of very low level of radioactivity. LEP is classified as Nuclear Basic Installation (Installation Nucléaire de Base, INB) in France, where no unconditional clearance levels are fixed for the specific activity in materials to be released into the public domain. In the case of LEP, the possible sources of induced activity taken here into account are: localised beam losses, distributed beam losses and synchrotron radiation. Reference values of induced specific activity at saturation, normalised to lost beam power, were determined by comparing Monte-Carlo calculations carried out with the FLUKA code and experimental results. These figures are directly employed to estimate the expected amount of low level radioactivity around localised beam loss points in LEP. Regarding the synchrotron radiation, calculations of the total production of radionuclides from photon, thermal neutron and fast neutron activation in the aluminium vacuum chamber, the lead shielding and the magnet pole-faces of a dipole, showed that at beam energies less than 105 GeV, none of the components will be considered as radioactive for decay periods of longer than ten days.

Consider a Hamiltonian system with $d$ degrees of freedom whose motions are all linear on tori of some fixed dimension $n\led$ is such a system necessarily completely (or else non-commutatively) integrable? We show that the answer is affirmative under quite broad conditions, but not always, and we provide counterexamples

The current paradigm of major histocompatibility complex (MHC) and disease association suggests that efficient binding of autoantigens by disease-associated MHC molecules leads to a T cell–mediated immune response and resultant autoimmune sequelae. The data presented below offer a different model for this association of MHC with autoimmune diabetes. We used several mouse lines expressing different levels of I-Ag7 and I-Ak on the nonobese diabetic (NOD) background to evaluate the role of MHC class II in the previously described NOD T cell autoproliferation. The ratio of I-Ag7 to I-Ak expression correlated with the peripheral T cell autoproliferative phenotype in the mice studied. T cells from the NOD, [NOD × NOD.I-Anull]F1, and NOD I-Ak transgenic mice demonstrated autoproliferative responses (after priming with self-peptides), whereas the NOD.H2h4 (containing I-Ak) congenic and [NOD × NOD.H2h4 congenic]F1 mice did not. Analysis of CD4+ NOD I-Ak transgenic primed lymph node cells showed that autoreactive CD4+ T cells in the NOD I-Ak transgenic mice were restricted exclusively by I-Ag7. Considered in the context of the avidity theory of T cell activation and selection, the reported poor peptide binding capacity of NOD I-Ag7 suggested a new hypothesis to explain the effects of MHC class II expression on the peripheral autoimmune repertoire in NOD mice. This new explanation suggests that the association of MHC with diabetes results from “altered” thymic selection in which high affinity self-reactive (potentially autoreactive) T cells escape negative selection. This model offers an explanation for the requirement of homozygous MHC class II expression in NOD mice (and in humans) in susceptibility to insulin-dependent diabetes mellitus.

Les problèmes de la dosimétrie dans les champs de rayonnements ionisants diffusés autour des accélérateurs de haute énergie sont présentés. Après une courte introduction sur l'historique des grandeurs physiques utilisées pour l'acquisition de l'équivalent de dose, les techniques diverses pour la dosimétrie dans des champs mixtes à haute énergie sont décrites, en commençant par des mesures spectrales compliquées, puis par la présentation des moyens en multidétecteurs et en instruments sur la base des détecteurs proportionnels. Enfin l'utilisation de méthodes simples est mise en évidence pour le cas où l'on dispose d'une connaissance initiale et supplémentaire sur la composition des rayonnements ionisants. Il est montré que les résultats des mesures correspondent bien à ceux obtenus à l'aide des programmes de calcul modernes.

Using simple known methods and results of classical perturbation theory, especially those due to Nekhoroshev and Neishtadt, we study the energy exchanges between the rotational and the translational degrees of freedom in a particular model representing the planar motion of a rigid body in a bounded analytic potential. We prove that, if the angular velocity? is initially large, then the energy exchanges are small,O(?-1), for times growing exponentially with?, |t|~exp?. We also deduce that in a scattering process from a (smooth) potential barrier, the overall change in the rotational energy of the incoming body is exponentially small in?, E~exp(-?. The results are interpreted in the light of an old conjecture by Boltzmann and Jeans on the existence of very large time scales for equilibrium in statistical systems containing high-frequency degrees of freedom (purely classical “freezing” of the high-frequency degrees of freedom); the rotating object is, in this interpretation, a (classical) molecule, which moves in an external field, or collides with the wall of a container. Two different limits of large? are considered, namely the limit of large rotational energy, and (as is interesting for the molecular interpretation) the limit of point mass, at finite rotational energy.

Summary: In the present paper, rupture detection in a possibly complex stochastic system is enhanced by means of a procedure for localizing the actual rupture among various possible sources. A general model is considered which includes a variety oflinear and non-linear innovation based models. The proposed localizing multiple comparison procedure satisfiescoherence andconsonance and, for a wide class of models, strongly controls the familywise error i.e. the various type I error probabilities involved. The first order autoregressive optimal control model is considered as a popular example. Montecarlo simulations are performed to evaluate asymptotic approximations and diagnostic performances by means of mean time of delay and mean time between false alarms. Some conjectures are then given on the possible structure of these indicators.

In this paper we discuss the relation between the structures of the series expansion for the Dragt and Finn composition of Lie transforms and for a transformation introduced by Giorgilli and Galgani. A recursive algorithm is presented which is used to generate the series expansion for the composition of Lie transforms. This algorithm strongly resembles the algorithm of Giorgilli and Galgani, and differs from it only in an ordering property. The relation with the algorithms of Kamel and Henrard for Deprit's direct and inverse series is also discussed.

The Advanced Photon Source (APS) currently under construction at Argonne National Laboratory will be one of the world's brightest synchrotron radiation (SR) facilities. The storage ring, capable of storing currents up to 300 mA at 7.0 GeV, or 200 mA at 7.5 GeV, will produce very intense and energetic synchrotron radiation (Ec= 24 keVfor bending magnets, and Ec= 37.4 keV for wigglers, where Ecis the critical energy). The synchrotron radiation beam lines, consisting of experimental enclosures and transport lines, will have to be shielded against synchrotron radiation and gas bremsstrahlung scattered from beam line components. For insertion devices placed in the straight sections (length = 15 m), the gas bremsstrahlung produced by the interaction of the primary stored beam with residual gas molecules or ions in the storage ring vacuum chamber dominates the SR beam line shielding. Gas bremsstrahlung in the forward direction will be stopped by a tungsten beam stop, 18cm thick, located at the back of the experimental enclosure and placed in the median plane of the storage ring. The forward-directed gas bremsstrahlung is characterized, and the effectiveness of the tungsten beam stop is assessed. The Monte Carlo code FLUKA was used to determine the dose equivalent rates from gas bremsstrahlung in a cylindrical tissue phantom with and without the tungsten beam stop. Simulations were performed using an air target of length 15 m at a pressure of 1 atm and 110atm(1 atm = 101.325 kPa = 760 torr) both with and without suppressing positron multiple scattering (M.S.) and Bhabha and Möller scattering in the air target. At a given pressure the dose equivalent rates are higher without positron multiple scattering in the air target than with multiple scattering. For simulations at Ps= 1 atm, the minimization of Bhabha/Möller scattering is important for areas with scoring radii less than 0.4 cm. The maximum dose equivalent rate (for E0= 7 Gev, I= 300 mA, and P= 0.133 μPaor 10−9torr) in the phantom (at a depth of 29.5 cm) for a scoring area of 0.0013 cm2(radius = 0.02 cm) is 2.1 Sv/h, whereas for a scoring area of 0.5 cm2(radius = 0.4 cm) it is 0.57 Sv/h. Scoring photon fluence and converting it to dose equivalent using Rogers' fluence-to-dose equivalent conversion factors results in an overestimation of dose equivalent. The maximum dose equivalent rate behind the tungsten beam stop, at a depth of 2.5 cm in the tissue, is 0.1 + 0.04 μSv/h for a scoring radius of 1 cm. The corresponding dose equivalent rates without the stop are 32 mSv/h (depth = 2.5 cm) and 0.17 Sv/h (depth = 29.5 cm). A simple expression has been derived for the upper limit on the dose equivalent that an individual can receive due to loss of vacuum in the straight section.

Abstract: We prove a conjecture by N.N. Nekhoroshev about the long-time stability of elliptic equilibria of Hamiltonian systems, without any Diophantine condition on the frequencies. Higher order terms of the Hamiltonian are used to provide convexity. The singularity of the action-angle coordinates at the origin is overcome by working in cartesian coordinates.

Unresponsiveness to self is maintained through two mechanisms of immune regulation: thymic-negative selection and peripheral tolerance. Although thymic-negative selection is a major mechanism to eliminate self-reactive T cells, normal mice have readily detectable populations of T cells reactive to self-proteins but do not exhibit autoimmune responses. It has been postulated that autoimmune disease results from breakdown or loss of peripheral tolerance. We present data that demonstrate that peripheral tolerance or unresponsiveness to self can be broken in nonobese diabetic (NOD) mice. Immunization of NOD mice (but not of conventional mice) with self-peptides caused an immune response to self-peptide with resultant autoproliferation of peripheral lymphocytes. Autoproliferation of self-reactive T cells in NOD mice resulted from the recognition and proliferation of the activated T cells to endogenously processed and presented self-antigens. This loss of self-tolerance demonstrated in vitro may well be the basis of NOD autoimmune disease in vivo.

This paper deals with Hamiltonian perturbation theory for systems which, like Euler-Poinsot (the rigid body with a fixed point and no torques), are degenerate and do not possess a global system of action-angle coordinates. It turns out that the usual methods of perturbation theory, which are essentially ‘local’ being based on the construction of normal forms within the domain of a local coordinate system, are not immediately usable to study perturbations of these systems, since degeneracy makes impossible to control that the system does not fall into a singularity of the coordinates. To overcome this difficulty, we develop a ‘global’ formulation of Hamiltonian perturbation theory, in which the normal forms are globally defined on the phase space manifold. The key for this study lies in the geometry of the fibration by the invariant tori of an integrable degenerate Hamiltonian system, which is described by some generalizations of the Liouville-Arnol'd theorem and is reviewed in the paper. As an application, we provide a ‘global’ formulation of Nekhoroshev's theorem on the stability for exponentially long times.

In this paper we exhibit a rigorous perturbation theory for nearly integrable Hamiltonian systems, based on the composition of Lie Transforms. Precisely, we first study the algorithm for the composition of Lie transforms, and provide rigorous estimates for the convergence radius and the truncation errors of the series; then we use our estimates for a particular model-example, namely a system of weakly coupled harmonic oscillators having Diophantine frequencies, and work out Nekhoroshev-like exponential estimates for the stability times.

We study the global structure of the fibration by the invariant two-dimensional tori of the Euler-Poinsot top — the rigid body with a fixed point and no torques. We base our analysis on the notion of bifibration (or dual pair) which, as results from the approach based on the so-called non-commutative integrability, provides a thorough description of the geometry of integrable degenerate Hamiltonian systems. In this way, we get a global geometric picture of the Euler-Poinsot system which fully accounts for its degeneracy through the (Poisson) structure of the base of the fibration by the two-dimensional invariant tori. In particular, we explain in this way why this system does not possess global ‘generalized’ action-angle coordinates: the obstructions are the topological non-triviality of the fibration by the invariant two-dimensional tori and the compactness of the symplectic leaves of its base manifold. We also compare this description with the usual description based on the notion of complete integrability, and we remark that, as a general fact, such a common approach fails to provide a natural, thorough description of degenerate systems.

We consider a rigorous Hamiltonian perturbation theory based on the transformation of the vector field of the system, realized by the Lie method. Such a perturbative technique presents some advantages over the standard one, which uses the transformation of the Hamilton functions. Indeed, the present method is simple, and furnishes quite detailed informations on the normal form. Moreover, it leads to estimates which are better and/or simpler than those of the scalar Lie methods. The perturbation method is presented with reference to two model problems, both pertaining to the realm of the well known Nekhoroshev theorem: the confining of actions for exponentially long times in a system of coupled harmonic oscillators, and an application to the so called problem of the realization of a holonomic constraint in classical mechanics.

We report that cryoablation of primary tumors synergizes with anti-CTLA-4 treatment to mediate rejection of secondary tumors in the TRAMP mouse model of prostate cancer. T cells, in particular CD8+T cells specific for the TRAMP antigen SPAS-1, were enriched in both secondary tumors and spleens of combination-treated mice.

Live-attenuated Listeria monocytogeneshas shown encouraging potential as an immunotherapy platform in preclinical and clinical settings. However, additional safety measures will enable application across malignant and infectious diseases. Here, we describe a new vaccine platform, termed Lm-RIID (L. monocytogenesrecombinase-induced intracellular death), that induces the deletion of genes required for bacterial viability yet maintains potent T cell responses to encoded antigens.

Bonner sphere spectrometers (BSSs) are employed in neutron spectrometry and dosimetry since many years. Recent developments have seen the addition to a conventional BSS of one or more detectors (moderator plus thermal neutron counter) specifically designed to improve the overall response of the spectrometer to neutrons above 10 MeV. These additional detectors employ a shell of material with a high mass number (such as lead) within the polyethylene moderator, in order to slow down high-energy neutrons via (n,xn) reactions. A BSS can be used to measure neutron spectra both outside accelerator shielding and from an unshielded target. Measurements were recently performed at CERN of the neutron yield and spectral fluence at various angles from unshielded, semi-thick copper, silver and lead targets, bombarded by a mixed proton/pion beam with 40 GeV per c momentum. These experiments have provided evidence that under certain circumstances, the use of lead-enriched moderators may present a problem: these detectors were found to have a significant response to the charged hadron component accompanying the neutrons emitted from the target. Conventional polyethylene moderators show a similar behaviour but less pronounced. These secondary hadrons interact with the moderator and generate neutrons, which are in turn detected by the counter. To investigate this effect and determine a correction factor to be applied to the unfolding procedure, a series of Monte Carlo simulations were performed with the FLUKA code. These simulations aimed at determining the response of the BSS to charged hadrons under the specific experimental situation. Following these results, a complete response matrix of the extended BSS to charged pions and protons was calculated with FLUKA. An experimental verification was carried out with a 120 GeV per c hadron beam at the CERF facility at CERN.

The responses of the Polish TLDs, MTS-N and MCP-N, are reported. Relative to 137Cs gamma rays, the response of MTS-N (natLiF:Mg,Ti - 0.04 cm thick) increased from 0.4 to 1.4 between X ray energies of 6 and 30 keV, and that of MCP-N (natLiF:Mg, Cu, P - 0.04 cm thick) increased from 0.2 to 1.2 between 6 and 26 keV. A mathematical model for TLD response was used with measured responses to determine overall TLD efficiency, C(k), and efficiency relative to 137Cs. The effective energy attenuation coefficient �(k) and light attenuation coefficient f were also determined experimentally. The relative efficiency of MTS-N increased from 0.66 to 1.30 between 6 and 30 keV and that of MCP-N increased from 0.37 to 0.99 between 6 and 26 keV.

Attenuation lengths for concrete and dose equivalent source terms for the shielding of electron beams in the GeV range are estimated on the basis of results of Monte Carlo calculations. Fair agreement is found with corresponding value from the literature. In particular, a value of 100 g.cm-2 for the lateral attenuation length of high energy particles seems to be a conservative value for electron accelerators compared with the even higher value of 115 g.cm-2 as a high energy limit for proton accelerators that had sometimes been recommended also for the shielding of GeV electron beams.