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Glioblastoma, the most common and lethal primary adult brain tumor, cannot be successfully removed surgically due to its highly invasive nature. Therapeutically, approaches must be aimed at a systemic brain disease and not merely at a tumor located within the brain, unless a successful containment strategy can be found. Reelin, an extracellular matrix glycoprotein, plays an important role in neuronal migration and serves here as a natural stop signal. Interestingly, the expression of reelin is negatively associated with tumor grade and, within glioblastoma, correlates with increased overall survival. To further elucidate a potential biological reason for these findings, we looked at the cellular behavior of glioblastoma cell lines grown on a pure fibronectin matrix or a matrix with reelin inserts. While reelin had no significant effects on cellular metabolism, proliferation, or resistance to chemotherapeutic agents, it did significantly affect the cells' interaction with fibronectin. Both matrix attachment and detachment were modulated by reelin, and thus, the invasion and motility of cells interacting with a reelin-containing matrix were altered. The data presented in this work strongly suggest that reelin might be a potential modulator of underlying molecular mechanisms that contribute to glioblastoma invasion.

Intense x-ray pulses can cause the non-thermal structural transformation of diamond. At the SACLA XFEL facility, pump x-ray pulses triggered this phase transition, and probe x-ray pulses produced diffraction patterns. Time delays were observed from 0 to 250 fs, and the x-ray dose varied from 0.9 to 8.0 eV/atom. The intensity of the (111), (220), and (311) diffraction peaks decreased with time, indicating a disordering of the crystal lattice. From a Debye-Waller analysis, the rms atomic displacements perpendicular to the (111) planes were observed to be significantly larger than those perpendicular to the (220) or (311) planes. At a long time delay of 33 ms, graphite (002) diffraction indicates that graphitization did occur above a threshold dose of 1.2 eV/atom. These experimental results are in qualitative agreement with XTANT+ simulations using a hybrid model based on density-functional tight-binding molecular dynamics., Competing Interests: The authors have no conflicts to disclose., (© 2023 Author(s).)

Alumina (Al 2 O 3 ) is an important ceramic material notable for its compressive strength and hardness. It represents one of the major oxide components of the Earth's mantle. Static compression experiments have reported evidence for phase transformations from the trigonal α -corundum phase to the orthorhombic Rh 2 O 3 (II)-type structure at ∼90 GPa, and then to the post-perovskite structure at ∼130 GPa, but these phases have yet to be directly observed under shock compression. In this work, we describe laser-driven shock compression experiments on polycrystalline alumina conducted at the Matter in Extreme Conditions endstation of the Linac Coherent Light Source. Ultrafast x-ray pulses (50 fs, 10 12 photons/pulse) were used to probe the atomic-level response at different times during shock propagation and subsequent pressure release. At 107 ± 8 GPa on the Hugoniot, we observe diffraction peaks that match the orthorhombic Rh 2 O 3 (II) phase with a density of 5.16 ± 0.03 g cm -3 . Upon unloading, the material transforms back to the α -corundum structure. Upon release to ambient pressure, densities are lower than predicted assuming isentropic release, indicating additional lattice expansion due to plastic work heating. Using temperature values calculated from density measurements, we provide an estimate of alumina's strength on release from shock compression., (© 2022 IOP Publishing Ltd.)

The newly constructed time-resolved atomic, molecular and optical science instrument (TMO) is configured to take full advantage of both linear accelerators at SLAC National Accelerator Laboratory, the copper accelerator operating at a repetition rate of 120 Hz providing high per-pulse energy as well as the superconducting accelerator operating at a repetition rate of about 1 MHz providing high average intensity. Both accelerators power a soft X-ray free-electron laser with the new variable-gap undulator section. With this flexible light source, TMO supports many experimental techniques not previously available at LCLS and will have two X-ray beam focus spots in line. Thereby, TMO supports atomic, molecular and optical, strong-field and nonlinear science and will also host a designated new dynamic reaction microscope with a sub-micrometer X-ray focus spot. The flexible instrument design is optimized for studying ultrafast electronic and molecular phenomena and can take full advantage of the sub-femtosecond soft X-ray pulse generation program., (open access.)

Since October 2020, the first digital health applications (DiGA) have been listed with the Federal Institute for Drugs and Medical Devices (BfArM) and can be prescribed by physicians and psychotherapists in the statutory health insurance system. In this article, four of the first BfArM-listed DiGA manufacturers report on their experiences with the BfArM Fast-Track procedure for DiGA, which enables listing from the time of application in just three months.Regarding the DiGA Fast-Track procedure and the cooperation with the BfArM, overall positive experiences are reported. However, applicants need to consider some points before and during the application process as well as after the positive decision. Before submitting the application, it is advisable to conduct audits to ensure that all requirements are met. BfArM consultations should be used, especially to clarify questions regarding proof of positive supply effect. Manufacturers should be prepared for numerous queries and follow-up requests from BfArM and be able to respond quickly. In the case of ambiguities, direct contact should be made with the BfArM. Manufacturers should note that sales of their product will not automatically follow a positive decision, as the medical profession still needs to be informed more fundamentally about DiGA and the path from the prescription to the activation of DiGA is currently still cumbersome. Manufacturers should also be prepared for continued interaction with BfArM after listing.Overall, manufacturers are recommended to cooperate early, proactively, openly, and closely with the BfArM because they themselves are liable for the information they provide in the application and the BfArM does not check all of it in detail., (© 2021. Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature.)

We present structure and equation of state (EOS) measurements of biaxially orientated polyethylene terephthalate (PET, [Formula: see text], also called mylar) shock-compressed to ([Formula: see text]) GPa and ([Formula: see text]) K using in situ X-ray diffraction, Doppler velocimetry, and optical pyrometry. Comparing to density functional theory molecular dynamics (DFT-MD) simulations, we find a highly correlated liquid at conditions differing from predictions by some equations of state tables, which underlines the influence of complex chemical interactions in this regime. EOS calculations from ab initio DFT-MD simulations and shock Hugoniot measurements of density, pressure and temperature confirm the discrepancy to these tables and present an experimentally benchmarked correction to the description of PET as an exemplary material to represent the mixture of light elements at planetary interior conditions.

Background: Identification of patients with lymphocytic variant hypereosinophilic syndrome (L-HES) is challenging, and has important prognostic and therapeutic implications., Objective: This study was undertaken to assess diagnostic tools for L-HES and to develop evidence-based diagnostic recommendations., Methods: Biomarkers of T-cell-driven disease were compared between patients with L-HES versus idiopathic HES (I-HES) variants. Those performed routinely (serum immunoglobulin levels, T-cell phenotyping, T-cell receptor [TCR] gene rearrangement patterns) were collected from medical files, whereas others were prospectively assessed on stored blood samples (serum CCL17/thymus and activation regulated chemokine [TARC] levels, in vitro cytokine production)., Results: This study included 48 patients with I-HES and 20 with L-HES associated with a CD3 - CD4 + T-cell subset, including 7 with less than 5% aberrant cells. Neither increased serum immunoglobulin levels nor clonal TCR gene rearrangements were sufficiently sensitive or specific for L-HES. In contrast, systematically enhanced expression of the T-cell surface antigens CD2, CD5, CD45RO, and CD95 by these cells allowed for accurate detection by flow cytometry. Serum CCL17/TARC levels were significantly higher in patients with L-HES compared with those with I-HES, and a threshold of 3000 pg/mL allowed for detection of all subjects with L-HES with 75% specificity. Quantification of intracytoplasmic cytokine production by flow cytometry is the most reliable method for detection of enhanced type 2 cytokine expression, most notably for IL-4 and IL-13., Conclusion: Adapting the standard of procedure for T-cell phenotyping in patients with unexplained hypereosinophilia is currently the most reliable means of identifying those with CD3 - CD4 + L-HES., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Ronchi testing of a focused electromagnetic wave has in the last few years been used extensively at X-ray free-electron laser (FEL) facilities to qualitatively evaluate the wavefront of the beam. It is a quick and straightforward test, is easy to interpret on the fly, and can be used to align phase plates that correct the focus of aberrated beams. In general, a single Ronchigram is not sufficient to gain complete quantitative knowledge of the wavefront. However the compound refractive lenses that are commonly used at X-ray FELs exhibit a strong circular symmetry in their aberration, and this can be exploited. Here, a simple algorithm that uses a single recorded Ronchigram to recover the full wavefront of a nano-focused beam, assuming circular symmetry, is presented, and applied to experimental measurements at the Matter in Extreme Conditions instrument at the Linac Coherent Light Source.

Purpose of Review: In this study, we will give an overview on the current and foreseeable indications of next-generation sequencing (NGS)-based technologies for the diagnosis, prognostic assessment and decision of individualized treatment strategy in lymphomas., Recent Findings: Recent NGS-based studies have offered a comprehensive knowledge of the genetic landscapes featuring B-cell and T-cell lymphomas, with identification of genomic biomarkers useful for a better subclassification and, therefore, for a more accurate diagnosis. NGS analyses in lymphoma have also unveiled recurrent somatic mutations representing novel potential therapeutic targets or underlying drug resistance, and paved the way for tailor-made medicine. High throughput sequencing methods may also identify lymphoma-specific genetic aberrations in circulating tumoral DNA (liquid biopsy) obtained from blood samples. This suggests the possibility of performing minimally invasive diagnosis and real-time monitoring, with early detection of relapse and possibility of response-adapted therapy approaches., Summary: NGS analyses should be included shortly in the diagnostic work up of lymphomas. Applying NGS to liquid biopsy at diagnosis and during follow up of lymphoma patients will be a significant breakthrough towards precision medicine.

Background: Lymphocytic variant hypereosinophilic syndrome is characterized by marked over-production of eosinophilopoietic factor(s) by dysregulated T cells leading to eosinophil expansion. In most cases, these T cells are clonal and express a CD3 - CD4 + phenotype. As this is a rare disorder, presenting manifestations, disease course, treatment responses, and outcome are not well-characterized. Materials and Methods: In this retrospective single-center observational study, we reviewed medical files of all patients with persistent hypereosinophilia seen between 1994 and 2019 in whom CD3 - CD4 + T cells were detected. Data collection included clinical and biological findings at presentation, treatment responses, disease course, and serial CD3 - CD4 + T cell counts. Results: Our cohort comprises 26 patients, including 2 with hypereosinophilia of undetermined significance. All 24 symptomatic patients had cutaneous lesions and/or angioedema, and fasciitis was present in several cases. The aberrant T cell subset represented 2% or less total lymphocytes in 11 subjects. TCR gene rearrangement patterns on whole blood were polyclonal in these cases, while they all had serum CCL17/TARC levels above 1,500 pg/ml. Disease manifestations were mild and did not require maintenance therapy in roughly one third of the cohort, while two thirds required long-term oral corticosteroids and/or second-line agents. Among these, interferon-alpha was the most effective treatment option with a response observed in 8/8 patients, one of whom was cured of disease. Treatment had to be interrupted in most cases however due to poor tolerance and/or development of secondary resistance. Anti-interleukin-5 antibodies reduced blood eosinophilia in 5/5 patients, but clinical responses were disappointing. A sub-group of 5 patients had severe treatment-refractory disease, and experienced significant disease- and treatment-related morbidity and mortality, including progression to T cell lymphoma in three. Conclusions: This retrospective longitudinal analysis of the largest monocentric cohort of CD3 - CD4 + T cell associated lymphocytic variant hypereosinophilic syndrome published so far provides clinicians confronted with this rare disorder with relevant new data on patient presentation and outcome that should help tailor therapy and follow-up to different levels of disease severity. It highlights the need for novel therapeutic options, especially for the subset of patients with severe treatment-refractory disease. Future research efforts should be made toward understanding CD3 - CD4 + T cell biology in order to develop new treatments that target primary pathogenic mechanisms., (Copyright © 2020 Carpentier, Verbanck, Schandené, Heimann, Trépant, Cogan and Roufosse.)

With the improvement of treatment methods in acute hematology malignancies, the development of sensitive tools for minimal residual disease assessment has become a priority. The monitoring of WT1 expression level by real-time quantitative PCR has been a standard for minimal residual disease evaluation in acute myeloid leukemia and, since 2009, has been optimized through a European LeukemiaNet effort in an established protocol with well-defined clinical end points. Building on the work of the European LeukemiaNet, this article reports the development of a novel, one-step duplex WT1/ABL1 droplet digital assay for WT1 overexpression detection. This assay provides accurate data with high precision and linearity, even at low-template concentration, while retaining strong correlation with the standardized method and therefore maintaining the framework to analyze the results in the context of acute myeloid leukemia patients., (Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Inflammation and dysregulation of the immune system are hallmarks of several neurodegenerative diseases. An activated immune response is considered to be the cause of myelin breakdown in demyelinating disorders. In the peripheral nervous system (PNS), myelin can be degraded in an autophagy-dependent manner directly by Schwann cells or by macrophages, which are modulated by T-lymphocytes. Here, we show that the NF-κB activator Pleckstrin homology containing family member 5 (Plekhg5) is involved in the regulation of both Schwann cell autophagy and recruitment of T-lymphocytes in peripheral nerves during motoneuron disease. Plekhg5 -deficient mice show defective axon/Schwann cell units characterized by myelin infoldings in peripheral nerves. Even at late stages, Plekhg5 -deficient mice do not show any signs of demyelination and inflammation. Using RNAseq, we identified a transcriptional signature for an impaired immune response in sciatic nerves, which manifested in a reduced number of CD4 + and CD8 + T-cells. These findings identify Plekhg5 as a promising target to impede myelin breakdown in demyelinating PNS disorders., (Copyright © 2020 Lüningschrör, Slotta, Heimann, Briese, Weikert, Massih, Appenzeller, Sendtner, Kaltschmidt and Kaltschmidt.)

Background: Treatment with anti-PD1 monoclonal antibodies improves the survival of metastatic melanoma patients but only a subgroup of patients benefits from durable disease control. Predictive biomarkers for durable benefit could improve the clinical management of patients., Methods: Plasma samples were collected from patients receiving anti-PD1 therapy for ctDNA quantitative assessment of BRAF V600 and NRAS Q61/G12/G13 mutations., Results: After a median follow-up of 84 weeks 457 samples from 85 patients were analyzed. Patients with undetectable ctDNA at baseline had a better PFS (Hazard ratio (HR) = 0.47, median 26 weeks versus 9 weeks, p = 0.01) and OS (HR = 0.37, median not reached versus 21.3 weeks, p = 0.005) than patients with detectable ctDNA. Additionally, the HR for death was lower after the ctDNA level became undetectable during follow-up (adjusted HR: 0.16 (95% CI 0.07-0.36), p-value < 0.001). ctDNA levels > 500 copies/ml at baseline or week 3 were associated with poor clinical outcome. Patients progressive exclusively in the central nervous system (CNS) had undetectable ctDNA at baseline and at subsequent assessments. In multivariate analysis adjusted for LDH, CRP, ECOG and number of metastatic sites, the ctDNA remained significant for PFS and OS. A positive correlation was observed between ctDNA levels and total metabolic tumor volume (TMTV), number of metastatic sites and total tumor burden., Conclusions: Assessment of ctDNA baseline and during therapy was predictive for tumor response and clinical outcome in metastatic melanoma patients and reflected the tumor burden. ctDNA evaluation provided reliable complementary information during anti-PD1 antibody therapy.

We investigated the high-pressure behavior of polyethylene (CH 2 ) by probing dynamically-compressed samples with X-ray diffraction. At pressures up to 200 GPa, comparable to those present inside icy giant planets (Uranus, Neptune), shock-compressed polyethylene retains a polymer crystal structure, from which we infer the presence of significant covalent bonding. The A2/m structure which we observe has previously been seen at significantly lower pressures, and the equation of state measured agrees with our findings. This result appears to contrast with recent data from shock-compressed polystyrene (CH) at higher temperatures, which demonstrated demixing and recrystallization into a diamond lattice, implying the breaking of the original chemical bonds. As such chemical processes have significant implications for the structure and energy transfer within ice giants, our results highlight the need for a deeper understanding of the chemistry of high pressure hydrocarbons, and the importance of better constraining planetary temperature profiles.

For LCLS-II, a fluorescence intensity monitor for the non-invasive, pulse-by-pulse normalization of experiments has been developed. A prototype diagnostic was constructed with a microchannel plate assembly and two photodiodes. The diagnostic was then installed in the LCLS SXR instrument Kirkpatrick-Baez mirror chamber with the detectors located above the vertically reflecting mirror. The linearity, noise and position sensitivity of the detectors have been characterized. The photodiode responsivity is suitable for high pulse energies. The microchannel plate detector shows sufficient responsivity over a wide range of pulse energies. The relative signal from the two photodiodes provides a sensitive measure of the X-ray beam position. The fluorescence intensity monitor provides intensity normalization while being compatible with high incident power, a 0.93 MHz repetition rate and ultra-high vacuum., (open access.)

[This corrects the article DOI: 10.1186/s13034-018-0239-y.].

Liver disease is a leading cause of morbidity and mortality worldwide. Recently, the liver non-parenchymal cells have gained increasing attention for their potential role in the development of liver disease. Liver sinusoidal endothelial cells (LSECs), a specialized type of endothelial cells that have unique morphology and function, play a fundamental role in maintaining liver homeostasis. Current protocols for LSEC isolation and cultivation rely on freshly isolated cells which can only be maintained differentiated in culture for a few days. This creates a limitation in the use of LSECs for research and a need for a consistent and reliable source of these cells. To date, no LSEC cryopreservation protocols have been reported that enable LSECs to retain their functional and morphological characteristics upon thawing and culturing. Here, we report a protocol to cryopreserve rat LSECs that, upon thawing, maintain full LSEC-signature features: fenestrations, scavenger receptor expression and endocytic function on par with freshly isolated cells. We have confirmed these features by a combination of biochemical and functional techniques, and super-resolution microscopy. Our findings offer a means to standardize research using LSECs, opening the prospects for designing pharmacological strategies for various liver diseases, and considering LSECs as a therapeutic target.

Background: This naturalistic study assesses the effectiveness of inpatient multidisciplinary treatment of children and adolescents with somatic symptom disorders (SSD) and investigates the role of pain coping strategies and psychiatric comorbidity (anxiety, depression)., Methods: Sixty children and adolescents (mean age 14.4 years) with SSD who underwent inpatient multidisciplinary treatment were assessed regarding their school attendance, levels of discomfort, coping strategies and psychiatric comorbidity (depression, anxiety) at pretreatment, discharge and 6 months following treatment., Results: At discharge, the children and adolescents reported improvements in their level of discomfort, psychiatric comorbidities (anxiety, depression) and pain coping strategies, with medium to large effect sizes. Six months following treatment, the improvements remained stable, including significantly higher school attendance rates ( d  = 1.6; p  < 0.01). Improvement in pain coping was associated with increased school attendance., Conclusion: Inpatient multidisciplinary treatment is effective in reducing levels of discomfort, psychiatric comorbidity (anxiety, depression), and school absence and in improving coping strategies.

Introduction: An IgM monoclonal gammopathy points to a diagnosis of Waldenstrom's Macroglobulinemia. Other B lymphoproliferatives disorders should be ruled out but the limits are sometimes difficult to define. The discovery of the L265P mutation of the MYD88 gene simplified potentially the situation., Population and Methods: 383 patients of the Jules Bordet Institute with an IgM level above 2 g/L were reviewed. For the 49 who had a monoclonal peak, we analysed the underlying pathology in termes of general, clinical and biological characteristics. We checked if the MYD88 mutation had been detected. The overall survival rate was studied., Results: 5 histological groups were identified: Waldenstrom's Macroglobulinemia (MW, N = 27), lymphoplasmacytic lymphoma (LLP, N = 10), marginal zone lymphoma (LMZ, N = 7), monoclonal gammopathy of unknown significance and multiple myeloma (MGUS/MM, N = 5). The MW group was compared to the other groups. Regarding biological characteristics, the IgM level upon diagnosis was statistically higher in the MW group with a median level at 19.5 g/L (2.3-101 g/L) (p-value = 0,0001). Concerning the clinical characteristics, a splenomegaly was more frequent in the LMZ group (p-value = 0,04). The L265P mutation of the MYD88 gene was found in 77 % of patients in the MW group, 60 % of patients in the LLP group and 67 % in the LMZ group (p-value = 0,38). For the 49 patients, the 10-yearoverall survival was 85 % (CI 95 %, 67 % to 94 %) and the 15-year-overall survival was 65 % (CI 95 %, 41 % to 81 %)., Conclusion: A monoclonal IgM peak suggests a MW but other B lymphoproliferatives disorders should be excluded. Even if the L265P mutation is frequent in the LLP/MW, it is not specific. A precise diagnosis requires collating clinical, histological, immunophenotypical and genetical data.

Predictive biomarkers are eagerly awaited in advanced colorectal cancer (aCRC). Targeted sequencing performed on tumor and baseline plasma samples in 20 patients with aCRC treated with regorafenib identified 89 tumor-specific mutations of which ≥50% are also present in baseline plasma. Droplet digital PCR (ddPCR) assays were optimized to monitor circulating tumor DNA (ctDNA) levels in plasmatic samples collected throughout the treatment course and showed the importance of using the absolute value for ctDNA rather than the mutant/wild type ratio in monitoring the therapy outcome. High baseline cell free DNA (cfDNA) levels are associated with shorter overall survival (OS) (HR 7.38, P=0.001). An early increase (D14) in mutated copies/mL is associated with a significantly worse PFS (HR 6.12, P=0.008) and OS (HR 8.02, P=0.004). These data suggest a high prognostic value for early ctDNA level changes and support the use of blood-born genomic markers as a tool for treatment., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

A retrospective study was performed to describe molecular responses (MR) on the international scale (IS) in patients with chronic myeloid leukemia (CML) treated with imatinib in routine clinical practice in Belgium and to identify patients potentially eligible for treatment discontinuation. The analysis included 116 patients with CML in chronic phase at treatment centers sending blood samples for molecular follow-up to a single EUTOS-certified laboratory. IS MR from the last patient visit between October 2014 and April 2015 were retrospectively collected. Most patients (93.1%) had an IS MR corresponding to an optimal response per European LeukemiaNet 2013 guidelines; 53.4% (62/116) of patients were in deep molecular responses ≥MR 4.5 at their last visit (mean treatment duration: 91.0 months) among whom 36.2% (42/116) had been receiving imatinib for >5.8 years and 26.7% (31/116) for >8 years (margins of error: 8.74% and 8.05%, respectively). These patients would likely have the highest chance of staying in treatment-free remission (TFR) upon discontinuation, based on published TFR trial data. Although our study only provides a snapshot in time of a patient's last MR reported, without precise information regarding MR duration, the study settings could nevertheless support the feasibility of attempting TFR outside clinical trials in the future., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Warm dense conditions in titanium foils irradiated with intense femtosecond laser pulses are diagnosed using an x-ray imaging spectroscopy technique. The line shapes of radially resolved titanium Kα spectra are measured with a toroidally bent GaAs crystal and an x-ray charge-coupled device. Measured spectra are compared with the K-shell emissions modeled using an atomic kinetics - spectroscopy simulation code. Kα line shapes are strongly affected by warm (5-40 eV) bulk electron temperatures and imply multiple temperature distributions in the targets. The spatial distribution of temperature is dependent on the target thickness, and a thin target shows an advantage to generate uniform warm dense conditions in a large area.

Anti-programmed death 1 (PD-1) monoclonal antibodies improve the survival of metastatic melanoma patients. Predictive or monitoring biomarkers for response to this therapy could improve the clinical management of these patients. To date, no established biomarkers are available for monitoring the response to immunotherapy. Tumor- specific mutations in circulating tumor DNA (ctDNA) such as BRAF and NRAS mutations for melanoma patients have been proposed for monitoring of immunotherapy response. We present seven illustrative cases for the use of ctDNA BRAF and NRAS mutations' monitoring in plasma. The cases described exemplify four distinct clinical benefit patterns: rapid and durable complete response (CR), early progression, followed by CR, CR followed by early progression after interrupting treatment and long-term disease stabilization. These representative cases suggest that comprehensive BRAF/NRAS ctDNA monitoring during anti-PD1 therapy is informative and can be of added value for the monitoring of melanoma patients gaining clinical benefit on anti-PD1 treatment. An important advantage of our approach is that using the cartridge system on the Idylla platform for mutation analysis, the results become available the same day 2 h after plasma collection. Therefore, in the future, the ctDNA level can be an element in the clinical management of the patients.

For the LCLS-II X-ray instruments, laser power meters are being developed as compact X-ray power diagnostics to operate at soft and tender X-ray photon energies. These diagnostics can be installed at various locations along an X-ray free-electron laser (FEL) beamline in order to monitor the transmission of X-ray optics along the beam path. In addition, the power meters will be used to determine the absolute X-ray power at the endstations. Here, thermopile power meters, which measure average power, and have been chosen primarily for their compatibility with the high repetition rates at LCLS-II, are evaluated. A number of characteristics in the soft X-ray range are presented including linearity, calibrations conducted with a photodiode and a gas monitor detector as well as ultra-high-vacuum compatibility tests using residual gas analysis. The application of these power meters for LCLS-II and other X-ray FEL sources is discussed.

Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures. Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease.

A nonlinear absorber in which the excited state absorption is larger than the ground state can undergo a process called reverse saturable absorption. It is a well-known phenomenon in laser physics in the optical regime, but is more difficult to generate in the x-ray regime, where fast nonradiative core electron transitions typically dominate the population kinetics during light matter interactions. Here, we report the first observation of decreasing x-ray transmission in a solid target pumped by intense x-ray free electron laser pulses. The measurement has been made below the K-absorption edge of aluminum, and the x-ray intensity ranges are 10^{16} -10^{17}  W/cm^{2}. It has been confirmed by collisional radiative population kinetic calculations, underscoring the fast spectral modulation of the x-ray pulses and charge states relevant to the absorption and transmission of x-ray photons. The processes shown through detailed simulations are consistent with reverse saturable absorption, which would be the first observation of this phenomena in the x-ray regime. These light matter interactions provide a unique opportunity to investigate optical transport properties in the extreme state of matters, as well as affording the potential to regulate ultrafast x-ray free-electron laser pulses.

Tuning the energy of an x-ray probe to an absorption line or edge can provide material-specific measurements that are particularly useful for interfaces. Simulated hard x-ray images above the Fe K-edge are presented to examine ion diffusion across an interface between Fe 2 O 3 and SiO 2 aerogel foam materials. The simulations demonstrate the feasibility of such a technique for measurements of density scale lengths near the interface with submicron spatial resolution. A proof-of-principle experiment is designed and performed at the Linac coherent light source facility. Preliminary data show the change of the interface after shock compression and heating with simultaneous fluorescence spectra for temperature determination. The results provide the first demonstration of using x-ray imaging at an absorption edge as a diagnostic to detect ultrafast phenomena for interface physics in high-energy-density systems.

Objective: In Lao People's Democratic Republic, the high burden of vaccine-preventable diseases is thought to be mainly due to low vaccine coverage. We investigated the seroprotective response against diphtheria-tetanus-whole cell pertussis-hepatitis B-Haemophilus influenzae type b (DTPw-HepB-Hib) vaccine in children., Methods: Serum was collected from 1131 children aged 9 to 50 months and their mothers in a cross-sectional study between December 2013 and July 2014. All children had records of three injections of the DTPw-HepB-Hib vaccine. Serum was analysed for hepatitis B surface antigen (HBsAg), anti-HBsAg (anti-HBs), anti-hepatitis B virus core antigen (anti-HBc), anti-diphtheria and anti-tetanus antibodies. Stool samples were collected for detection of parasites. Demographic and nutritional information were also obtained., Results: Protective levels of anti-HBs antibodies were found in 394 (37.9%) of 1039 children; 529 (55.7%) of 950 and 809 (85.2%) of 950 children were seroprotected against diphtheria and tetanus. Time since vaccination, age, home birth and malnutrition only partially explained the poor vaccine responses. Overall, 81 (7.8%) of 1039 children and 445 (40.3%) of 1105 of mothers were anti-HBc positive. Ten (1.0%) of 1039 of the children and 77 (7.0%) of 1105 of the mothers were HBsAg carriers., Conclusions: After a full documented course of vaccination, seroprotective rates were unusually low and disparate against components of the pentavalent vaccine. These can only partially be explained by the negative predictors identified. Although many children had been infected, only few were chronic carriers of HBsAg. Our study demonstrates an urgent need to monitor the serologic response to vaccination, particularly in resource-poor countries., (Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Ultrahigh energy cosmic ray air showers probe particle physics at energies beyond the reach of accelerators. Here we introduce a new method to test hadronic interaction models without relying on the absolute energy calibration, and apply it to events with primary energy 6-16 EeV (E&#95;{CM}=110-170  TeV), whose longitudinal development and lateral distribution were simultaneously measured by the Pierre Auger Observatory. The average hadronic shower is 1.33±0.16 (1.61±0.21) times larger than predicted using the leading LHC-tuned models EPOS-LHC (QGSJetII-04), with a corresponding excess of muons.

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8±0.7(stat)±6.7(syst)  MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principles calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.

The effect of a dense plasma environment on the energy levels of an embedded ion is usually described in terms of the lowering of its continuum level. For strongly coupled plasmas, the phenomenon is intimately related to the equation of state; hence, an accurate treatment is crucial for most astrophysical and inertial-fusion applications, where the case of plasma mixtures is of particular interest. Here we present an experiment showing that the standard density-dependent analytical models are inadequate to describe solid-density plasmas at the temperatures studied, where the reduction of the binding energies for a given species is unaffected by the different plasma environment (ion density) in either the element or compounds of that species, and can be accurately estimated by calculations only involving the energy levels of an isolated neutral atom. The results have implications for the standard approaches to the equation of state calculations.

The performance of X-ray free-electron laser beamlines may be limited by the angular aperture. Compound refractive lenses (CRLs) can be employed to prefocus the X-ray beam, thereby increasing the beamline transmission. A prefocusing CRL was implemented in the X-ray transport of the Matter under Extreme Conditions Instrument at the Linac Coherent Light Source. A significant improvement in the beamline transmission was calculated over the 3-10 keV photon energy range. At 5 keV, the relative X-ray intensity was measured and a factor of four increase was seen in the beamline transmission. The X-ray focus was also determined by the ablation imprint method.

Experimental investigation of electron-ion coupling and electron heat capacity of copper in warm and dense states are presented. From time-resolved x-ray absorption spectroscopy, the temporal evolution of electron temperature is obtained for non-equilibrium warm dense copper heated by an intense femtosecond laser pulse. Electron heat capacity and electron-ion coupling are inferred from the initial electron temperature and its decrease over 10 ps. Data are compared with various theoretical models.

Chronic eosinophilic leukaemia associated with the FIP1L1-PDGFRA fusion gene (F/P+ CEL) is a rare cause of marked persistent hypereosinophilia, arising almost exclusively in male patients. Clinical presentations are heterogeneous with a higher incidence of eosinophil-mediated cardiomyopathy than in other hypereosinophilic syndrome variants. Features of chronic myeloproliferative disease are often present, including splenomegaly and elevated serum vitamin B12 levels. The diagnosis is made by fluorescence in situ hybridization (FISH) showing the deletion of the CHIC2 locus and/or RT-PCR showing the FIP1L1-PDGFRA fusion transcript. Treatment with imatinib mesylate, a tyrosine kinase inhibitor, results in rapid and complete resolution of hypereosinophilia and associated symptoms, except for those related to sub-endocardial fibrosis that may be irreversible. We report the case of a male patient in whom isolated intractable cough remained the only clinical manifestation of F/P+ CEL for 4 years. Furthermore, eosinophil autofluorescence, an as yet unreported artefact in this setting, precluded the detection of the CHIC2 deletion and further delayed diagnosis, underlining that both FISH and RT-PCR should be performed when this disease is suspected., (© 2016 S. Karger AG, Basel.)

Cell membranes are composed of 2D bilayers of amphipathic lipids, which allow a lateral movement of the respective membrane components. These components are arranged in an inhomogeneous manner as transient micro- and nanodomains, which are believed to be crucially involved in the regulation of signal transduction pathways in mammalian cells. Because of their small size (diameter 10-200 nm), membrane nanodomains cannot be directly imaged using conventional light microscopy. Here, direct visualization of cell membrane nanodomains by helium ion microscopy (HIM) is presented. It is shown that HIM is capable to image biological specimens without any conductive coating and that HIM images clearly allow the identification of nanodomains in the ultrastructure of membranes with 1.5 nm resolution. The shape of these nanodomains is preserved by fixation of the surrounding unsaturated fatty acids while saturated fatty acids inside the nanodomains are selectively removed. Atomic force microscopy, fluorescence microscopy, 3D structured illumination microscopy, and direct stochastic optical reconstruction microscopy provide additional evidence that the structures in the HIM images of cell membranes originate from membrane nanodomains. The nanodomains observed by HIM have an average diameter of 20 nm and are densely arranged with a minimal nearest neighbor distance of ≈ 15 nm., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Recently, Next Generation Sequencing (NGS) has begun to supplant other technologies for gene mutation testing that is now required for targeted therapies. However, transfer of NGS technology to clinical daily practice requires validation., Methods: We validated the Ion Torrent AmpliSeq Colon and Lung cancer panel interrogating 1850 hotspots in 22 genes using the Ion Torrent Personal Genome Machine. First, we used commercial reference standards that carry mutations at defined allelic frequency (AF). Then, 51 colorectal adenocarcinomas (CRC) and 39 non small cell lung carcinomas (NSCLC) were retrospectively analyzed., Results: Sensitivity and accuracy for detecting variants at an AF >4% was 100% for commercial reference standards. Among the 90 cases, 89 (98.9%) were successfully sequenced. Among the 86 samples for which NGS and the reference test were both informative, 83 showed concordant results between NGS and the reference test; i.e. KRAS and BRAF for CRC and EGFR for NSCLC, with the 3 discordant cases each characterized by an AF <10%., Conclusions: Overall, the AmpliSeq colon/lung cancer panel was specific and sensitive for mutation analysis of gene panels and can be incorporated into clinical daily practice.

Malignant lymphoma and other lymphoproliferative disorders represent a group of malignant hemopathies where immunotherapy has allowed spectacular progresses over the last ten years. The recent W.H.O. classification, based upon tumor immunology, and cytogenetical anomalies, allows a better identification of each lymphoma and the comparison of homogeneous populations within various clinical studies. The increase in the incidence of non-Hodgkin lymphoma is related to the aging of the population as well as to other factors that are still to be analysed - a real challenge for the future. We have tried to offer an overview of the latest therapeutical advances while focusing on the major role of general practitioner. The most frequency askeed questions will be discussed.

The LCLS beam provides revolutionary capabilities for studying the transient behavior of matter in extreme conditions. The particular strength of the Matter in Extreme Conditions instrument is that it combines the unique LCLS beam with high-power optical laser beams, and a suite of dedicated diagnostics tailored for this field of science. In this paper an overview of the beamline, the capabilities of the instrumentation, and selected highlights of experiments and commissioning results are presented.

The Soft X-ray Research instrument provides intense ultrashort X-ray pulses in the energy range 280-2000 eV. A diverse set of experimental stations may be installed to investigate a broad range of scientific topics such as ultrafast chemistry, highly correlated materials, magnetism, surface science, and matter under extreme conditions. A brief description of the main instrument components will be given, followed by some selected scientific highlights.

Deficiency of arylsulfatase G (ARSG) leads to a lysosomal storage disease in mice resembling biochemical and pathological features of the mucopolysaccharidoses and particularly features of mucopolysaccharidosis type III (Sanfilippo syndrome). Here we show that Arsg KO mice share common neuropathological findings with other Sanfilippo syndrome models and patients, but they can be clearly distinguished by the limitation of most phenotypic alterations to the cerebellum, presenting with ataxia as the major neurological finding. We determined in detail the expression of ARSG in the central nervous system and observed highest expression in perivascular macrophages (which are characterized by abundant vacuolization in Arsg KO mice) and oligodendrocytes. To gain insight into possible mechanisms leading to ataxia, the pathology in older adult mice (>12 months) was investigated in detail. This study revealed massive loss of Purkinje cells and gliosis in the cerebellum, and secondary accumulation of glycolipids like GM2 and GM3 gangliosides and unesterified cholesterol in surviving Purkinje cells, as well as neurons of some other brain regions. The abundant presence of ubiquitin and p62-positive aggregates in degenerating Purkinje cells coupled with the absence of significant defects in macroautophagy is consistent with lysosomal membrane permeabilization playing a role in the pathogenesis of Arsg-deficient mice and presumably Sanfilippo disease in general. Our data delineating the phenotype of mucopolysaccharidosis IIIE in a mouse KO model should help in the identification of possible human cases of this disease., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The rate at which atoms and ions within a plasma are further ionized by collisions with the free electrons is a fundamental parameter that dictates the dynamics of plasma systems at intermediate and high densities. While collision rates are well known experimentally in a few dilute systems, similar measurements for nonideal plasmas at densities approaching or exceeding those of solids remain elusive. Here we describe a spectroscopic method to study collision rates in solid-density aluminium plasmas created and diagnosed using the Linac Coherent light Source free-electron X-ray laser, tuned to specific interaction pathways around the absorption edges of ionic charge states. We estimate the rate of collisional ionization in solid-density aluminium plasmas at temperatures ~30 eV to be several times higher than that predicted by standard semiempirical models.

The Linac Coherent Light Source has added a self-seeding capability to the soft x-ray range using a grating monochromator system. We report the demonstration of soft x-ray self-seeding with a measured resolving power of 2000-5000, wavelength stability of 10(-4), and an increase in peak brightness by a factor of 2-5 across the photon energy range of 500-1000 eV. By avoiding the need for a monochromator at the experimental station, the self-seeded beam can deliver as much as 50-fold higher brightness to users.

High-intensity x-ray pulses from an x-ray free-electron laser are used to heat and probe a solid-density aluminum sample. The photon-energy-dependent transmission of the heating beam is studied through the use of a photodiode. Saturable absorption is observed, with the resulting transmission differing significantly from the cold case, in good agreement with atomic-kinetics simulations.

Energy-dependent patterns in the arrival directions of cosmic rays are searched for using data of the Pierre Auger Observatory. We investigate local regions around the highest-energy cosmic rays with [Formula: see text] eV by analyzing cosmic rays with energies above [Formula: see text] eV arriving within an angular separation of approximately 15[Formula: see text]. We characterize the energy distributions inside these regions by two independent methods, one searching for angular dependence of energy-energy correlations and one searching for collimation of energy along the local system of principal axes of the energy distribution. No significant patterns are found with this analysis. The comparison of these measurements with astrophysical scenarios can therefore be used to obtain constraints on related model parameters such as strength of cosmic-ray deflection and density of point sources.

Unlabelled: Transient neonatal leukemia occurs almost exclusively in Down syndrome babies. We report here the unusual case of a newborn without Down syndrome who presented neonatal transient leukemia and who achieved spontaneously complete remission. Trisomy 21 and GATA1 mutation were both present in leukemic cells. While close follow-up is advised since true leukemia may develop later, the patient is still in remission for 2.5 years. We performed a literature review of 15 other similar cases., Conclusion: Our case of transient leukemia without Down syndrome and the literature review highlight the important role of trisomy 21 and GATA1 mutation in the development of transient neonatal leukemia.

We have developed a new experimental platform at the Linac Coherent Light Source (LCLS) which combines simultaneous angularly and spectrally resolved x-ray scattering measurements. This technique offers a new insights on the structural and thermodynamic properties of warm dense matter. The < 50 fs temporal duration of the x-ray pulse provides near instantaneous snapshots of the dynamics of the compression. We present a proof of principle experiment for this platform to characterize a shock-compressed plastic foil. We observe the disappearance of the plastic semi-crystal structure and the formation of a compressed liquid ion-ion correlation peak. The plasma parameters of shock-compressed plastic can be measured as well, but requires an averaging over a few tens of shots.

Recent experiments performed at the Matter in Extreme Conditions end station of the Linac Coherent Light Source (LCLS) have demonstrated the first spectrally resolved measurements of plasmons from isochorically heated aluminum. The experiments have been performed using a seeded 8-keV x-ray laser beam as a pump and probe to both volumetrically heat and scatter x-rays from aluminum. Collective x-ray Thomson scattering spectra show a well-resolved plasmon feature that is down-shifted in energy by 19 eV. In addition, Mbar shock pressures from laser-compressed aluminum foils using velocity interferometer system for any reflector have been measured. The combination of experiments fully demonstrates the possibility to perform warm dense matter studies at the LCLS with unprecedented accuracy and precision.