Ionization potentials of metal clusters studied with a broad range, tunable vacuum ultraviolet light source.

In this work, we present an alternative to complex laser setups or synchrotron light sources to accurately measure the ionization potentials of metal clusters. The setup is based on a commercial Xe flash lamp, combined with a vacuum monochromator, and has been applied to determine the ionization potentials of Snn clusters with n = 8-12 atoms. The uncertainty in the determination of the ionization potentials is mainly caused by the bandwidth of the monochromator. The adiabatic ionization potentials (AIPs) are extracted from experimental photoionization efficiency curves. Franck-Condon simulations are additionally used to interpret the shape and onset of the photo-ion yield. The obtained AIPs are (all energies are in eV) Sn8 (6.53 ± 0.05), Sn9 (6.69 ± 0.04), Sn10 (6.93 ± 0.03), Sn11 (6.34 ± 0.05), and Sn12 (IsoI 6.64 ± 0.04 and IsoIII 6.36 ± 0.05). Furthermore, the impact of multiple isomers present in the experiment on the photo-ion yield is addressed and compared with other experimental data in the literature.

Characterization of LiF:Mg,Ti thermoluminescence detectors in low-LET proton beams at ultra-high dose rates.

Objective.This work aims at characterizing LiF:Mg,Ti thermoluminescence detectors (TLDs) for dosimetry of a 250 MeV proton beam delivered at ultra-high dose rates (UHDR). Possible dose rate effects in LiF:Mg,Ti, as well as its usability for dosimetry of narrow proton beams are investigated.Approach.LiF:Mg,Ti (TLD-100TMMicrocubes, 1 mm × 1 mm × 1 mm) was packaged in matrices of 5 × 5 detectors. The center of each matrix was irradiated with single-spot low-LET (energy >244 MeV) proton beam in the (1-4500) Gy s-1average dose rates range. A beam reconstruction procedure was applied to the detectors irradiated at the highest dose rate (Gaussian beam sigma <2 mm) to correct for volumetric averaging effects. Reference dosimetry was carried out with a diamond detector and radiochromic films. The delivered number of protons was measured by a Faraday cup, which was employed to normalize the detector responses.Main results.The lateral beam spread obtained from the beam reconstruction agreed with the one derived from the radiochromic film measurements. No dose rates effects were observed in LiF:Mg,Ti for the investigated dose rates within 3% (k= 1). On average, the dose response of the TLDs agreed with the reference detectors within their uncertainties. The largest deviation (-5%) was measured at 4500 Gy s-1.Significance.The dose rate independence of LiF:Mg,Ti TLDs makes them suitable for dosimetry of UHDR proton beams. Additionally, the combination of a matrix of TLDs and the beam reconstruction can be applied to determine the beam profile of narrow proton beams.

Ultra-high dose rate dosimetry for pre-clinical experiments with mm-small proton fields.

PURPOSE: To characterize an experimental setup for ultra-high dose rate (UHDR) proton irradiations, and to address the challenges of dosimetry in millimetre-small pencil proton beams. METHODS: At the PSI Gantry 1, high-energy transmission pencil beams can be delivered to biological samples and detectors up to a maximum local dose rate of âˆ¼9000 Gy/s. In the presented setup, a Faraday cup is used to measure the delivered number of protons up to ultra-high dose rates. The response of transmission ion-chambers, as well as of different field detectors, was characterized over a wide range of dose rates using the Faraday cup as reference. RESULTS: The reproducibility of the delivered proton charge was better than 1 % in the proposed experimental setup. EBT3 films, Al2O3:C optically stimulated luminescence detectors and a PTW microDiamond were used to validate the predicted dose. Transmission ionization chambers showed significant volume ion-recombination (>30 % in the tested conditions) which can be parametrized as a function of the maximum proton current density. Over the considered range, EBT3 films, inorganic scintillator-based screens and the PTW microDiamond were demonstrated to be dose rate independent within ±3 %, ±1.8 % and ±1 %, respectively. CONCLUSIONS: Faraday cups are versatile dosimetry instruments that can be used for dose estimation, field detector characterization and on-line dose verification for pre-clinical experiments in UHDR proton pencil beams. Among the tested detectors, the commercial PTW microDiamond was found to be a suitable option to measure real time the dosimetric properties of narrow pencil proton beams for dose rates up to 2.2 kGy/s.

Unleashing the full power of LHCb to probe stealth new physics.

In this paper, we describe the potential of the LHCb experiment to detect stealth physics. This refers to dynamics beyond the standard model that would elude searches that focus on energetic objects or precision measurements of known processes. Stealth signatures include long-lived particles and light resonances that are produced very rarely or together with overwhelming backgrounds. We will discuss why LHCb is equipped to discover this kind of physics at the Large Hadron Collider and provide examples of well-motivated theoretical models that can be probed with great detail at the experiment.

Design of a compact and versatile radiation heater with an additively manufactured Nb radiation shield for UHV high-temperature sample preparation.

A compact, ultrahigh vacuum, radiative heater based on pyrolytic boron nitride that efficiently directs nearly all of its radiation to the sample was designed and constructed. It is shown that the heater reaches temperatures of 1300 K experimentally at 60% of its maximum power. A COMSOL Multiphysics® simulation and an analytical model predict an ultimate temperature of up to 1500 K. Furthermore, the heater does not introduce any contamination to the sample. This is accomplished by a custom-made Nb radiation shield, which was manufactured by selective laser melting and holds a flag-style sample holder. Before manufacturing, the whole assembly was simulated with COMSOL Multiphysics to validate the design of the radiation shield.

[TEG-guided treatment of a dabigatran overdose in a patient with acute kidney failure]. / TEG-unterstützte Therapie einer Dabigatranüberdosierung bei einem Patienten mit akutem Nierenversagen.

This article presents the case of a multimorbid male patient with an accidental dabigatran overdose caused by kidney failure in the context of an acute intestinal disorder. After effective initial antagonizing of the dabigatran effect using idarucizumab a dabigatran rebound was detected caused by a single hemodialysis leading to a severe intrapulmonary hemorrhage. As dabigatran plasma level testing was not available and conventional coagulation analysis was out of interpretable range due to the impact of dabigatran, continuous thrombelastography (TEG) was used to detect the effect of dabigatran and monitor the treatment results. The most significant parameter used in the kaolin activated clotting time was the R­time parameter, which was massively prolonged by the interrupted coagulation cascade.

Extended evaluation of the efficacy of a proactive forced oscillation technique-based auto-CPAP algorithm.

PURPOSE: Previous studies revealed substantially varying therapy efficacy of automatic continuous positive airway pressure (APAP) devices in the treatment of obstructive sleep apnea (OSA). We evaluated the efficacy of a new APAP device using the forced oscillation technique (FOT) to evaluate upper airway obstruction during apneas and flow contour analyses during hypopneas. METHODS: Forty-six initially diagnosed OSA patients were included and the pressure range was set from 5 to 20 hPa. Therapy efficacy was assessed based on the reduction of apnea-hypopnea index (AHI), improvement of objective sleep quality parameters, and the appropriateness of the device's pressure regulation. RESULTS: AHI and arousal index significantly decreased during APAP therapy (median [interquartile range]: AHI 36 [23-55] vs. 2 [1-6]/h, arousal index 30 [22-45] vs. 15 [10-19]/h, both p < 0.001). The amount of slow wave sleep (SWS) and rapid-eye-movement (REM) sleep significantly increased (SWS 20 [14-29] vs. 29 [19-34]%, REM 16 [11-21] vs. 24 [14-30]%, both p < 0.01). Most residual respiratory events during therapy were of central etiology and attributable to five patients, who presented with treatment-emergent central sleep apnea. The device's pressure regulation abolished most obstructive respiratory events (n = 6.7 residual obstructive events per patient). Of central respiratory events, 534/646 (83%) did not lead to pressure increases. CONCLUSION: This pilot study provides a proof of concept that the APAP device combining FOT and evaluation of flow contour allows for the suppression of obstructive events without relevant false reactions.

[RAS mutations at the molecular tumor conference]. / RAS-Mutationen in der molekularen Tumorkonferenz.

Members of the rat sarcoma (RAS) gene family belong to the most frequently mutated genes that drive pathogenesis and therapy response. As the discovery of their malignant potential dates back more than three decades, cellular mutated RAS genes and their products belong to the best characterized cancer genes. Despite urgent clinical needs, RAS therapies are still elusive and limited to preclinical studies. However, very recently, novel and promising approaches have become a reality in clinical applications and trials. In the near future, interesting therapeutic options will emerge that are capable of targeting "undruggable" RAS. This will be even more important as the detection of RAS mutations has already been an integral part of routine molecular diagnostics for many years.

The Refeeding Syndrome revisited: you can only diagnose what you know.

BACKGROUND/OBJECTIVES: The Refeeding Syndrome (RFS) is a serious complication in patients receiving nutrition support after a period of severe malnutrition. We frequently recognize and diagnose the RFS due to increased awareness. Thus, we observe that many physicians do not know the RFS and that it is rarely diagnosed. The aim of the study was to determine whether physicians in Germany know the RFS. SUBJECTS/METHODS: A questionnaire with a case vignette about an older person who developed the RFS after initiation of nutritional therapy was submitted to German physicians and fifth year medical students, who were participants of educational lectures. RESULTS: Of the 281 participants who answered the respective question, 40 participants (14%) correctly diagnosed the RFS of the case vignette and 21 participants (8%) gave nearly correct answers. Indeed, the majority of the participants did not diagnose the RFS. CONCLUSIONS: Although the RFS may lead to fatal complications, it is unknown to the majority of the queried physicians. Therefore, there is a call to implement the RFS in respective curricula and increase systematic education on this topic.

Spin-orbit effects in optical spectra of gold-silver trimers.

Cationic gold-silver trimers are ideal model systems for the evaluation of relativistic electronic structure theories. The closed-shell triangles allow one to test density functional and wavefunction-based methods in their prediction of optical properties, as dependent on composition and symmetry. Here we present the gas-phase optical spectra of AgNAu3-N+ (N = 0-3) clusters recorded by longitudinal photodissociation spectroscopy in the photon energy range 1.9-4.4 eV. The experimental data are compared to excited electronic state calculations in the framework of all-electron range-separated time-dependent density functional and equation-of-motion coupled cluster theory using two-component as well as the spin-free scalar relativistic theories. In particular, it is shown that for mixed trimers scalar-relativistic corrections are insufficient and a two-component approach becomes obligatory for a correct description of optical response properties including both spin-orbit coupling and charge-transfer effects.

Selective sensitivity in Kerr microscopy.

A new technique for contrast separation in wide-field magneto-optical Kerr microscopy is introduced. Utilizing the light from eight light emitting diodes, guided to the microscope by glass fibers and being switched synchronously with the camera exposure, domain images with orthogonal in-plane sensitivity can be displayed simultaneously at real-time, and images with pure in-plane or polar contrast can be obtained. The benefit of this new method of contrast separation is demonstrated for Permalloy films, a NdFeB sinter magnet, and a cobalt crystal. Moreover, the new technique is shown to strongly enhance the sensitivity of Kerr microscopy by eliminating parasitic contrast contributions occurring in conventional setups. A doubling of the in-plane domain contrast and a sensitivity to Kerr rotations as low as 0.6 mdeg is demonstrated.

Electrostatic simulation of a complete cluster deposition apparatus.

A complete electrostatic model of a cluster deposition apparatus is presented using SIMION. It consists of fifteen different ion optical components including a quadrupole mass filter and a quadrupole ion deflector. The accuracy of the model was tested by comparing calculated cationic cluster transmissions with experimental ion currents by varying the electrostatic potential of different components. Considering the negatively charged particles produced by the magnetron cluster source as a charged background with a density of 5⋅10-7 cm-3, the influence of the first components on cluster transmission is well reproduced in comparison to the experimental results. This background was included by increasing the charge of the clusters from zero to an elementary charge using a sigmoidal function. The inflection point of this function was found to depend on the first components' electrostatic potential but in good approximation, not on later ones. All of the calculated transmissions represent the experimental data quite well; therefore, the simulation is validated and helps us to understand the influence of the electrostatic components on cluster transmission and improve the target efficiency. Furthermore, this understanding opens the possibility for a global optimization scheme to be employed in the ion optics' geometries.

The role of the cancer stem cell marker CD271 in DNA damage response and drug resistance of melanoma cells.

Several lines of evidence have suggested that stemness and acquired resistance to targeted inhibitors or chemotherapeutics are mechanistically linked. Here we observed high cell surface and total levels of nerve growth factor receptor/CD271, a marker of melanoma-initiating cells, in sub-populations of chemoresistant cell lines. CD271 expression was increased in drug-sensitive cells but not resistant cells in response to DNA-damaging chemotherapeutics etoposide, fotemustine and cisplatin. Comparative analysis of melanoma cells engineered to stably express CD271 or a targeting short hairpin RNA by expression profiling provided numerous genes regulated in a CD271-dependent manner. In-depth analysis of CD271-responsive genes uncovered the association of CD271 with regulation of DNA repair components. In addition, gene set enrichment analysis revealed enrichment of CD271-responsive genes in drug-resistant cells, among them DNA repair components. Moreover, our comparative screen identified the fibroblast growth factor 13 (FGF13) as a target of CD271, highly expressed in chemoresistant cells. Further we show that levels of CD271 determine drug response. Knock-down of CD271 in fotemustine-resistant cells decreased expression of FGF13 and at least partly restored sensitivity to fotemustine. Together, we demonstrate that expression of CD271 is responsible for genes associated with DNA repair and drug response. Further, we identified 110 CD271-responsive genes predominantly expressed in melanoma metastases, among them were NEK2, TOP2A and RAD51AP1 as potential drivers of melanoma metastasis. In addition, we provide mechanistic insight in the regulation of CD271 in response to drugs. We found that CD271 is potentially regulated by p53 and in turn is needed for a proper p53-dependent response to DNA-damaging drugs. In summary, we provide for the first time insight in a CD271-associated signaling network connecting CD271 with DNA repair, drug response and metastasis.

[Mesenchymal stem/stroma cells : Therapeutic potential in the treatment of autoimmune diseases]. / Mesenchymale Stamm-/Stromazellen : Therapeutisches Potenzial in der Behandlung von Autoimmunerkrankungen.

Mesenchymal stem and stromal cells (MSC) are propagated for the treatment of autoimmune and autoinflammatory processes. These cells can be relatively easily obtained from various tissues. The MSC feature anti-inflammatory and immunosuppressive properties in vitro as well as in animal models. Initial reports on the clinical application of MSC for various diseases are available, some with promising results and so far no reported toxicity; however, data from phase III studies are still lacking and crucial questions are still unanswered. The MSC preparations used are heterogeneous and also differ depending on the source and it is unclear whether autologous (own) or allogeneic (foreign) MSC are more suitable for therapeutic use. Long-term consequences, such as possible malignant transformation and possible endogenous tumor growth stimulation cannot be completely excluded. Ultimately, these questions can only be answered through randomized controlled trials for defined clinical indications with defined MSC.

Uncoupling of EGFR-RAS signaling and nuclear localization of YBX1 in colorectal cancer.

The transcription factor YBX1 can act as a mediator of signals transmitted via the EGFR-RAS-MAPK axis. YBX1 expression has been associated with tumor progression and prognosis in multiple types of cancer. Immunohistochemical studies have revealed dependency between YBX1 expression and individual EGFR family members. We analyzed YBX1 and EGFR family proteins in a colorectal cancer (CRC) cohort and provide functional analyses of YBX1 in the context of EGFR-RAS-MAPK signaling. Immunohistochemistry for YBX1 and EGFR family receptors with two antibodies for YBX1 and EGFR were performed and related to clinicopathological data. We employed Caco2 cells expressing an inducible KRASV12 gene to determine effects on localization and levels of YBX1. Mouse xenografts of Caco2-KRASV12 cells were used to determine YBX1 dynamics in a tissue context. The two different antibodies against YBX1 showed discordant immunohistochemical stainings in cell culture and clinical specimens. Expression of YBX1 and EGFR family members were not correlated in CRC. Analysis of Caco2 xenografts displayed again heterogeneity of YBX1 staining with both antibodies. Our results suggest that YBX1 is controlled via complex regulatory mechanisms involving tumor stroma interaction and signal transduction processes. Our study highlights that YBX1 antibodies have different specificities, advocating their use in a combined manner.

Pathogen-reduced Ebola virus convalescent plasma: first steps towards standardization of manufacturing and quality control including assessment of Ebola-specific neutralizing antibodies.

BACKGROUND: Ebola virus disease is a public health emergency of international concern, and enormous efforts are being made in the development of vaccines and therapies. Ebola virus convalescent plasma is a promising anti-infective treatment of Ebola virus disease. Therefore, we developed and implemented a pathogen-reduced Ebola virus convalescent plasma concept in accordance with national, European and global regulatory framework. MATERIALS AND METHODS: Ebola virus convalescent plasma manufacture and distribution was managed by a collection centre, two medical centres and an expert group from the European Blood Alliance. Ebola virus convalescent plasma was collected twice with an interval of 61 days from a donor recovering from Ebola virus disease in Germany. After pathogen reduction, the plasma was analysed for Ebola virus-specific immunoglobulin G (IgG) antibodies and its Ebola virus neutralizing activity. RESULTS: Convalescent plasma could be collected without adverse events. Anti-Ebola virus IgG titres and Ebola-specific neutralizing antibodies in convalescent plasma were only slightly reduced after pathogen reduction treatment with S59 amotosalen/UVA. A patient in Italy with Ebola virus disease was treated with convalescent plasma without apparent adverse effects. DISCUSSION: As proof of principle, we describe a concept and practical implementation of pathogen-reduced Ebola virus convalescent plasma manufacture, quality control and its clinical application to an Ebola virus disease patient.

Charge-induced dipole vs. relativistically enhanced covalent interactions in Ar-tagged Au-Ag tetramers and pentamers.

Vibrational spectra of Au(n)Ag(m)(+)⋅Ar(k) (n + m = 4, 5; k = 1-4) clusters are determined by far-infrared resonant multiple photon dissociation spectroscopy in the range ν̃=100-250 cm(-1). The experimental spectra are assigned using density functional theory for geometries obtained by the Birmingham cluster genetic algorithm. Putative global minimum candidates of the Ar complexes are generated by adding Ar atoms to the Au(n)Ag(m)(+) low energy isomers and subsequent local optimization. Differential Ar binding energies indicate exceptionally strong Au-Ar bonds in Au-rich clusters, leading to fundamental changes to the IR spectra. The stronger Ar binding is attributed to a relativistically enhanced covalent character of the Au-Ar bond, while in Au-rich species charge-induced dipole interactions overcompensate the relativistic affinity to Au. Moreover, not only the absolute composition but also the topologies are essential in the description of Ar binding to a certain cluster.