SVEP1 influences monocyte to macrophage differentiation via integrin α4ß1/α9ß1 and Rho/Rac signalling.

BACKGROUND: The large extracellular matrix protein SVEP1 mediates cell adhesion via integrin α9ß1. Recent studies have identified an association between a missense variant in SVEP1 and increased risk of coronary artery disease (CAD) in humans and in mice Svep1 deficiency alters the development of atherosclerotic plaques. However how SVEP1 functionally contributes to CAD pathogenesis is not fully understood. Monocyte recruitment and differentiation to macrophages is a key step in the development of atherosclerosis. Here, we investigated the requirement for SVEP1 in this process. METHODS: SVEP1 expression was measured during monocyte-macrophage differentiation in primary monocytes and THP-1 human monocytic cells. SVEP1 knockout THP-1 cell lines and the dual integrin α4ß1/α9ß1 inhibitor, BOP, were utilised to investigate the effect of these proteins in THP-1 cell adhesion, migration and cell spreading assays. Subsequent activation of downstream integrin signalling intermediaries was quantified by western blotting. RESULTS: SVEP1 gene expression increases in monocyte to macrophage differentiation in human primary monocytes and THP-1 cells. Using two SVEP1 knockout THP-1 cells we observed reduction in monocyte adhesion, migration, and cell spreading compared to control cells. Similar results were found with integrin α4ß1/α9ß1 inhibition. We demonstrate reduced activity of Rho and Rac1 in SVEP1 knockout THP-1 cells. CONCLUSIONS: SVEP1 regulates monocyte recruitment and differentiation phenotypes through an integrin α4ß1/α9ß1 dependent mechanism. GENERAL SIGNIFICANCE: These results describe a novel role for SVEP1 in monocyte behaviour relevant to CAD pathophysiology.

Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial.

BACKGROUND: Given the young age of patients with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive, functional, and quality-of-life impairment with the current aggressive standard of care treatment, chemoradiation with PCV, of the tumour located in the brain optimizing care is the major challenge. METHODS: NOA-18 aims at improving qualified overall survival (qOS) for adult patients with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and temozolomide (CETEG) (n = 182 patients per group accrued over 4 years) thereby delaying radiotherapy and adding the chemoradiotherapy concept at progression after initial radiation-free chemotherapy, allowing for effective salvage treatment and delaying potentially deleterious side effects. QOS represents a new concept and is defined as OS without functional and/or cognitive and/or quality of life deterioration regardless of whether tumour progression or toxicity is the main cause. The primary objective is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine, and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event concerning a sustained qOS is then defined as a functional and/or cognitive and/or quality of life deterioration after completion of primary therapy on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with a 3-monthly MRI, assessment of the NANO scale, HRQoL, and KPS, and annual cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at a minimum of 18 NOA study sites in Germany. DISCUSSION: qOS represents a new concept. The present NOA trial aims at showing the superiority of CETEG plus RT-PCV over RT-PCV plus BIC as determined at the level of OS without sustained functional deterioration for all patients with oligodendroglioma diagnosed according to the most recent WHO classification. TRIAL REGISTRATION: Clinicaltrials.gov NCT05331521 . EudraCT 2018-005027-16.

Angular dependence of the transverse Raman scattering in KDP and DKDP in geometries suitable for beam polarization control.

The angular dependance of the transverse Raman scattering in potassium dihydrogen phosphate (KDP) and its deuterated analogue (DKDP) for the entire range of crystal configurations suitable for laser beam polarization control has been investigated via experimental and modeling tools. This work was made possible by simultaneously rotating a spherical sample and the pump polarization to effectively measure the angular dependance of the transverse Raman signal in 360°. This novel method, which is applicable for the investigation of the Raman scattering in optically anisotropic materials, demonstrates that the spontaneous Raman scattering signal exhibits strong angular dependence that is modulated by depolarization and polarization rotation effects generated as the Raman signal traverses the material due to its birefringence. The results show that the total signal generated by the pump beam is the sum of the signals generated by the two components that have polarization parallel and orthogonal to the optic axis. The peak signal intensity, which is of importance for high-power laser applications, depends on the orientation of the optic axis and can vary by a factor of about 2. The excellent agreement between experimental data and modeling results validates the associated models and enables one to consider optimal crystal cut designs for specific applications.

Magnetization transfer ratio: a quantitative imaging biomarker for 5q spinal muscular atrophy.

BACKGROUND AND PURPOSE: We quantified peripheral nerve lesions in adults with 5q-linked spinal muscular atrophy (SMA) type 3 by analysing the magnetization transfer ratio (MTR) of the sciatic nerve, and tested its potential as a novel biomarker for macromolecular changes. METHODS: Eighteen adults with SMA 3 (50% SMA 3a, 50% SMA 3b) and 18 age-/sex-matched healthy controls prospectively underwent magnetization transfer contrast imaging in a 3-Tesla magnetic resonance scanner. Two axial three-dimensional gradient echo sequences, with and without an off-resonance saturation rapid frequency pulse, were performed at the right distal thigh. Sciatic nerve regions of interest were manually traced on 10 consecutive axial slices in the images generated without off-resonance saturation, and then transferred to corresponding slices generated by the sequence with the off-resonance saturation pulse. Subsequently, MTR and cross-sectional areas (CSAs) of the sciatic nerve were analysed. In addition, detailed neurologic, physiotherapeutic and electrophysiologic examinations were conducted in all patients. RESULTS: Sciatic nerve MTR and CSA reliably differentiated between healthy controls and SMA 3, 3a or 3b. MTR was lower in the SMA 3 (P < 0.0001), SMA 3a (P < 0.0001) and SMA 3b groups (P = 0.0020) than in respective controls. In patients with SMA 3, MTR correlated with all clinical scores, and arm nerve compound motor action potentials (CMAPs). CSA was lower in the SMA 3 (P < 0.0001), SMA 3a (P < 0.0001) and SMA 3b groups (P = 0.0006) than in controls, but did not correlate with clinical scores or electrophysiologic results. CONCLUSIONS: Magnetization transfer ratio is a novel imaging marker that quantifies macromolecular nerve changes in SMA 3, and positively correlates with clinical scores and CMAPs.

Determination of the Raman polarizability tensor in the optically anisotropic crystal potassium dihydrogen phosphate and its deuterated analog.

The Raman tensor of the dominant A1 modes of the nonlinear optical crystalline material potassium dihydrogen phosphate and its 70% deuterated analog have been ascertained. Challenges in determining the A1 mode tensor element values based on previous reports have been resolved using a specially designed experimental setup that makes use of spherical crystal samples. This novel experimental design enabled the determination of measurement artifacts, including polarization rotation of the pump and/or scattered light propagating through the sample and the contribution of additional overlapping phonon modes, which have hindered previous efforts. Results confirmed that the polarization tensor is diagonal, and matrix elements were determined with high accuracy.

Mechanisms of picosecond laser-induced damage in common multilayer dielectric gratings.

The modifications of multilayer dielectric (MLD) gratings arising from laser-induced damage using 0.6-ps and 10-ps laser pulses at 1053 nm are investigated to better understand the damage-initiation mechanisms. Upon damage initiation, sections of the affected grating pillars are removed, thereby erasing the signature of the underlying mechanisms of laser damage. To address this issue, we performed paired studies using macroscopic grating-like features that are 5 mm in width to reveal the laser-damage morphology of the different grating sections: pillar side wall, sole, and pillar top. The results suggest that, similarly to MLD coatings, there are two damage-initiation mechanisms corresponding to the different pulse durations.

Inferred UV fluence focal-spot profiles from soft x-ray pinhole-camera measurements on OMEGA.

A method was developed with laser-irradiated Au planar foils to characterize the focal spot of UV laser beams on a target at full energy from soft x-ray emission. A pinhole camera with a back-thinned charge-coupled device detector and filtration with thin Be and Al foil filters provides images of the x-ray emission at photon energies <2 keV. This method requires a careful measurement of the relationship between the applied UV fluence and the x-ray signal, which can be described by a power-law dependence. The measured exponent γ ∼ 2 provides a dynamic range of ∼25 for the inferred UV fluence. UV fluence profiles of selected beams were measured for 100-ps and 1-ns laser pulses and were compared to directly measured profiles from an UV equivalent-target-plane diagnostic. The inferred spot size and super-Gaussian order from the x-ray technique agree within several percent with the values measured with the direct UV measurements.

Measurement of the angular dependence of the spontaneous Raman scattering in anisotropic crystalline materials using spherical samples: Potassium dihydrogen phosphate as a case example.

A specialized experimental configuration was developed to allow for more-accurate characterization of the spontaneous Raman scattering properties in anisotropic materials. This need stems from the challenges, arising from the complexity of light propagation, in obtaining accurate measurements of the angular dependence of the Raman scattering cross section in birefringent materials. The nonlinear optical material KH2PO4 (KDP) is used as a model medium. This study is motivated by the need to improve our understanding and management of transverse stimulated Raman scattering in KDP crystals and its deuterated analog, DKDP, typically used for frequency conversion and polarization control in large-aperture laser systems. Key to this experimental platform is the use of high-quality spherical samples that enable one to measure the Raman scattering cross section in a wide range of geometries using only a single sample. The effect of polarization rotation of both the pump light and the collected Raman signal must be carefully considered in data analysis and can give rise to artifacts, which can, in part, be mitigated by reducing the input and collection cone angles.

Effect of Linearization in a WNT Signaling Model.

A nonlinear model consisting of a system of coupled ordinary differential equations (ODE), describing a biological process linked with cancer development, is linearized using Taylor series and tested against different magnitudes of input perturbations, in order to investigate the extent to which the linearization is accurate. The canonical wingless/integrated (WNT) signaling pathway is considered. The linearization procedure is described, and special considerations for linearization validity are analyzed. The analytical properties of nonlinear and linearized systems are studied, including aspects such as existence of steady state and initial value sensitivity. Linearization is a useful tool for speeding up drug response computations or for providing analytical answers to problems such as required drug concentrations. A Monte Carlo-based error testing workflow is employed to study the errors introduced by the linearization for different input conditions and parameter vectors. The deviations between the nonlinear and the linearized system were found to increase in a polynomial fashion w.r.t. the magnitude of tested perturbations. The linearized system closely followed the original one for perturbations of magnitude within 10% of the base input vector which yielded the state-space fixed point used for the linearization.

Simulation of internal stress waves generated by laser-induced damage in multilayer dielectric gratings.

Multilayer dielectric (MLD) gratings used in ultrahigh-intensity laser systems often exhibit a laser-induced damage performance below that of their constituent materials. Reduced performance may arise from fabrication- and/or design-related issues. Finite element models were developed to simulate stress waves in MLD grating structures generated by laser-induced damage events. These models specifically investigate the influence of geometric and material parameters on how stress waves can lead to degradation of material structural integrity that can have adverse effects on its optical performance under subsequent laser irradiation: closer impedance matching of the layer materials reduces maximum interface stresses by ~20% to 30%; increasing sole thickness from 50 nm to 500 nm reduces maximum interface stresses by ~50%.

Raman Amplification with a Flying Focus.

We propose a new laser amplifier scheme utilizing stimulated Raman scattering in plasma in conjunction with a "flying focus"-a chromatic focusing system combined with a chirped pump beam that provides spatiotemporal control over the pump's focal spot. Pump intensity isosurfaces are made to propagate at v=-c so as to be in sync with the injected counterpropagating seed pulse. By setting the pump intensity in the interaction region to be just above the ionization threshold of the background gas, an ionization wave is produced that travels at a fixed distance ahead of the seed. Simulations show that this will make it possible to optimize the plasma temperature and mitigate many of the issues that are known to have impacted previous Raman amplification experiments, in particular, the growth of precursors.

An atlas of bloodstream-accessible bone marrow proteins for site-directed therapy of acute myeloid leukemia.

The concept of arming antibodies with bioactive payloads for a site-specific therapy of cancer has gained considerable interest in recent years. However, a successful antibody-based targeting approach critically relies on the availability of a tumor-associated target that is not only preferentially expressed in the tumor tissue but is also easily accessible for antibody therapeutics coming from the bloodstream. Here, we perfused the vasculature of healthy and acute myeloid leukemia (AML)-bearing rats with a reactive ester derivative of biotin and subsequently quantified the biotinylated proteins to identify AML-associated bone marrow (BM) antigens accessible from the bloodstream. In total, >1400 proteins were identified. Overall, 181 proteins were >100-fold overexpressed in AML as compared with normal BM. Eleven of the most differentially expressed proteins were further validated by immunohistochemistry and confocal microscopic analyses, including novel antigens highly expressed in AML cells (for example, adaptor-related protein complex 3 ß2) and in the leukemia-modified extracellular matrix (ECM) (for example, collagen-VI-α-1). The presented atlas of targetable AML-associated BM proteins provides a valuable basis for the development of monoclonal antibodies that could be used as carriers for a site-specific pharmacodelivery of cytotoxic drugs, cytokines or radionuclides to the BM in AML.

[Neuromodulation of lower urinary tract dysfunction]. / Neuromodulation bei Harnblasenfunktionsstörungen.

Neuromodulative procedures such as transcutaneous electrical nerve stimulation (TENS), transcutaneous/percutaneous tibial nerve stimulation (TTNS/PTNS), and sacral neuromodulation (SNM) are promising second-line treatments for refractory lower urinary tract dysfunction. Using these therapies, both storage and voiding disorders but also bowel dysfunction might be successfully treated. Although the mechanism of action of neuromodulation is not well understood, it seems to involve modulation of spinal cord reflexes and brain networks by peripheral afferents (genital/rectal, tibial and sacral afferents in the case of TENS, TTNS/PTNS, and SNM, respectively). Neuromodulative procedures might also be highly effective in the most desperate situations and further relevant developments are expected so that these innovative techniques will most likely become even more important in urology.

[Genetic testing in polygenic diseases : Atrial fibrillation, arterial hypertension and coronary artery disease]. / Genetische Diagnostik polygener Erkrankungen : Vorhofflimmern, Hypertonie und koronare Herzerkrankung.

Genetic testing plays an increasing role in cardiovascular medicine. Advances in technology and the development of novel and more affordable (high throughput) methods have led to the identification of genetic risk factors in research and clinical practice. Also, this progress has simplified the screening of patients and individuals at risk. In case of rare monogenic diseases, diagnostics, risk stratification, and, in some cases, treatment decisions have become easier. For common, polygenic cardiovascular diseases, the situation is more complex due to interaction of modifiable external risk factors and nonmodifiable factors like genetic predisposition. Over the last few years, it has been shown that multiple genes are involved in the pathophysiology of these cardiovascular diseases rather than one single gene. In the following article, we give an overview of the genetic risk factors in polygenic cardiovascular diseases as atrial fibrillation, arterial hypertension and coronary artery disease. Furthermore, we aim to illustrate in which cases genetic testing is recommended in these diseases.

Publisher's Note: Demonstration of Fuel Hot-Spot Pressure in Excess of 50 Gbar for Direct-Drive, Layered Deuterium-Tritium Implosions on OMEGA [Phys. Rev. Lett. 117, 025001 (2016)].

This corrects the article DOI: 10.1103/PhysRevLett.117.025001.

Demonstration of Fuel Hot-Spot Pressure in Excess of 50 Gbar for Direct-Drive, Layered Deuterium-Tritium Implosions on OMEGA.

A record fuel hot-spot pressure P_{hs}=56±7 Gbar was inferred from x-ray and nuclear diagnostics for direct-drive inertial confinement fusion cryogenic, layered deuterium-tritium implosions on the 60-beam, 30-kJ, 351-nm OMEGA Laser System. When hydrodynamically scaled to the energy of the National Ignition Facility, these implosions achieved a Lawson parameter ∼60% of the value required for ignition [A. Bose et al., Phys. Rev. E 93, 011201(R) (2016)], similar to indirect-drive implosions [R. Betti et al., Phys. Rev. Lett. 114, 255003 (2015)], and nearly half of the direct-drive ignition-threshold pressure. Relative to symmetric, one-dimensional simulations, the inferred hot-spot pressure is approximately 40% lower. Three-dimensional simulations suggest that low-mode distortion of the hot spot seeded by laser-drive nonuniformity and target-positioning error reduces target performance.

Urodynamic investigations in patients with spinal cord injury: should the ice water test follow or precede the standard filling cystometry?

OBJECTIVES: To evaluate whether the ice water test (IWT) should be performed before or after the standard urodynamic investigation (UDI). PATIENTS AND METHODS: Two cohorts of patients suffering from neurogenic lower urinary tract dysfunction (NLUTD) due to spinal cord injury (SCI) were matched by lesion level and age. The patients of cohort A (n=55, retrospective cohort) underwent the IWT before and the patients of cohort B (n=110, prospective cohort) after standard UDI. The IWT effect on urodynamic parameters has been compared between the two groups using the Mann-Whitney U-test for independent samples. UDI was performed according to good urodynamic practices recommended by the International Continence Society. RESULTS: The mean age of both cohorts was 49 years. Performing the IWT before versus after standard UDI resulted in a significantly lower maximum cystometric bladder capacity (P=0.01), lower incidence of detrusor overactivity (P=0.017) and lower maximum detrusor pressure during IWT (P=0.04). All other urodynamic parameters assessed demonstrated no significant difference (P>0.05). CONCLUSIONS: Our results are in line with findings from animal studies demonstrating a bladder cooling-induced gating effect on the micturition reflex volume threshold on the level of sacral interneurons. Since the IWT is an unphysiological investigation that might significantly bias subsequent urodynamics, we suggest that the IWT should not precede more physiological standard UDI.

Treatment strategies in patients with AML or high-risk myelodysplastic syndrome relapsed after Allo-SCT.

Non-relapse mortality after Allo-SCT has significantly decreased over the last years. Nevertheless, relapse remains a major cause for post SCT mortality in patients with AML and high-risk myelodysplastic syndrome (MDS). In this retrospective single-center analysis, we have analyzed the treatment outcomes of 108 patients with AML or MDS, who relapsed after Allo-SCT. Seventy of these patients (65%) were treated with salvage therapies containing chemotherapy alone, allogeneic cell-based treatment or the combination of both. Thirty-eight patients (35%) received palliative treatment. Median OS after diagnosis of relapse was 130 days. Compared with patients who received chemotherapy alone, response to salvage therapy was significantly improved in patients treated with a combination of chemo- and allogeneic cell-based therapy (CR rate 57% vs 13%, P=0.002). Among risk factors concerning pretreatment characteristics, disease status before first Allo-SCT, and details of transplantation, only the time interval from Allo-SCT to relapse was an independent predictor of response to salvage therapy and OS. These data confirmed that time to relapse after transplantation is an important prognostic factor. Up to now, only patients eligible for treatment regimens containing allogeneic cell-based interventions achieved relevant response rates.

Low ALT blood levels predict long-term all-cause mortality among adults. A historical prospective cohort study.

BACKGROUND: Increased blood levels of alanine amino transferase (ALT, also known as SGPT; serum glutamic pyruvic transaminase) serve as a marker of liver injury by various mechanisms. Less is known about the clinical implications associated with low-normal ALT levels. Previous studies showed low ALT levels to be associated with poor long-term outcomes among elderlies, serving as a biomarker for increased incidence of frailty and subsequent risk of mortality. However, it has not been determined yet whether low-normal ALT values might be predictive of frailty and mortality in younger, middle-aged adults. METHODS: We conducted a historical prospective cohort analysis. RESULTS: A total of 23,506 adults with ALT levels within the normal range, at the mean age of 48 ± 11 years, participating in an annual screening program for preventive medicine, were followed-up for a median period of 8.5 years during which 638 died. Low-normal ALT values (serum ALT activity <17IU/L) were found to be predictive for increased risk of all-cause mortality (HR=1.6; 95% CI 1.34-1.92; p<0.001). Statistically significant correlation was demonstrated even after applying a multifactorial model correction for age, gender, eGFR, low albumin, arterial hypertension, diabetes mellitus and ischemic heart disease. CONCLUSIONS: We suggest that low-normal ALT values may serve as an independent predictive marker for increased long-term mortality in middle-aged adults.