CXCL13 as a biomarker in the diagnostics of European lyme Neuroborreliosis - A prospective multicentre study in Austria.

Background: 'Definite Neuroborreliosis (NB)' is diagnosed with the presence of NB-specific symptoms, cerebrospinal fluid (CSF) pleocytosis and an elevated Borrelia Burgdorferi antibody index. However, some diagnostic uncertainties exist. The B-cell chemokine CXCL13 represents an emerging biomarker for the diagnosis and treatment of NB because its intrathecal concentration rises prior to the Borrelia antibody index and drops rapidly after antibiotic therapy. Nevertheless, due to lacking prospective data, a definite CXCL13 cut-off for the diagnosis of NB is still pending. Objective: Definition of a CSF CXCL13 cut-off for the diagnosis of acute and untreated NB in a prospective study setting. Design and methods: This multicentre prospective study involved 6 neurological departments treating patients in the Lower Austria district (1.7 million inhabitants). The controls were patients scheduled for a spinal tap but not clinically diagnosed with NB. Demographic data, clinical characteristics and blood counts, as well as inflammatory CSF values and CSF CXCL13-concentration were analysed. Results: We recruited 440 adult patients, of whom 42 have been diagnosed as having an acute and untreated 'definite NB'. Three hundred ninety-eight patients were assigned to the control group. The median intrathecal CXCL13 concentration was 2384 pg/ml for patients with NB and 0 pg/ml for controls. The difference was highly statistically significant (P ≤ .001). A CSF CXCL13 cut-off of 271 pg/ml resulted in a sensitivity of 95.2% and a specificity of 97.2% for the confirmation or exclusion of NB. Conclusion: Based on our results, we propose a CSF CXCL13 cut-off of 271 pg/ml with Euroimmun-Elisa for the diagnosis of acute and untreated NB. Due to its high sensitivity and specificity, CXCL13 is a strong candidate biomarker for routine NB assessment, especially in clinically unclear cases.

A novel function of STAT3ß in suppressing interferon response improves outcome in acute myeloid leukemia.

Signal transducer and activator of transcription 3 (STAT3) is frequently overexpressed in patients with acute myeloid leukemia (AML). STAT3 exists in two distinct alternatively spliced isoforms, the full-length isoform STAT3α and the C-terminally truncated isoform STAT3ß. While STAT3α is predominantly described as an oncogenic driver, STAT3ß has been suggested to act as a tumor suppressor. To elucidate the role of STAT3ß in AML, we established a mouse model of STAT3ß-deficient, MLL-AF9-driven AML. STAT3ß deficiency significantly shortened survival of leukemic mice confirming its role as a tumor suppressor. Furthermore, RNA sequencing revealed enhanced STAT1 expression and interferon (IFN) signaling upon loss of STAT3ß. Accordingly, STAT3ß-deficient leukemia cells displayed enhanced sensitivity to blockade of IFN signaling through both an IFNAR1 blocking antibody and the JAK1/2 inhibitor Ruxolitinib. Analysis of human AML patient samples confirmed that elevated expression of IFN-inducible genes correlated with poor overall survival and low STAT3ß expression. Together, our data corroborate the tumor suppressive role of STAT3ß in a mouse model in vivo. Moreover, they provide evidence that its tumor suppressive function is linked to repression of the STAT1-mediated IFN response. These findings suggest that the STAT3ß/α mRNA ratio is a significant prognostic marker in AML and holds crucial information for targeted treatment approaches. Patients displaying a low STAT3ß/α mRNA ratio and unfavorable prognosis could benefit from therapeutic interventions directed at STAT1/IFN signaling.

Favorable impact of PD1/PD-L1 antagonists on bone remodeling: an exploratory prospective clinical study and ex vivo validation.

BACKGROUND: Skeletal morbidity in patients with cancer has a major impact on the quality of life, and preserving bone health while improving outcomes is an important goal of modern antitumor treatment strategies. Despite their widespread use in early disease stages, the effects of immune checkpoint inhibitors (ICIs) on the skeleton are still poorly defined. Here, we initiated a comprehensive investigation of the impact of ICIs on bone health by longitudinal assessment of bone turnover markers in patients with cancer and by validation in a novel bioengineered 3D model of bone remodeling. METHODS: An exploratory longitudinal study was conducted to assess serum markers of bone resorption (C-terminal telopeptide, CTX) and formation (procollagen type I N-terminal propeptide, PINP, and osteocalcin, OCN) before each ICI application (programmed cell death 1 (PD1) inhibitor or programmed death-ligand 1 (PD-L1) inhibitor) for 6 months or until disease progression in patients with advanced cancer and no evidence of bone metastases. To validate the in vivo results, we evaluated osteoclast (OC) and osteoblast (OB) differentiation on treatment with ICIs. In addition, their effect on bone remodeling was assessed by immunohistochemistry, confocal microscopy, and proteomics analysis in a dynamic 3D bone model. RESULTS: During the first month of treatment, CTX levels decreased sharply but transiently. In contrast, we observed a delayed increase of serum levels of PINP and OCN after 4 months of therapy. In vitro, ICIs impaired the maturation of preosteoclasts by inhibiting STAT3/NFATc1 signaling but not JNK, ERK, and AKT while lacking any direct effect on osteogenesis. However, using our bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity on exposure to ICIs by demonstrating impaired OC maturation along with increased OB differentiation. CONCLUSION: Our study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with bone turnover and may exert a protective effect on bone by indirectly promoting osteogenesis.

Prospective Analysis of Radiation-Induced Contrast Enhancement and Health-Related Quality of Life After Proton Therapy for Central Nervous System and Skull Base Tumors.

PURPOSE: Intracerebral radiation-induced contrast enhancement (RICE) can occur after photon as well as proton beam therapy (PBT). This study evaluated the incidence, characteristics, and risk factors of RICE after PBT delivered to, or in direct proximity to, the brain and its effect on health-related quality of life (HRQoL). METHODS AND MATERIALS: Four hundred twenty-one patients treated with pencil beam scanning PBT between 2017 and 2021 were included. Follow-up included clinical evaluation and contrast-enhanced magnetic resonance imaging at 3, 6, and 12 months after treatment completion and annually thereafter. RICE was graded according to Common Terminology Criteria for Adverse Events version 4, and HRQoL parameters were assessed via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 questionnaires. RESULTS: The median follow-up was 24 months (range, 6-54), and median dose to 1% relative volume of noninvolved central nervous system (D1%CNS) was 54.3 Gy relative biologic effectiveness (RBE; range, 30-76 Gy RBE). The cumulative RICE incidence was 15% (n = 63), of which 10.5% (n = 44) were grade 1, 3.1% (n = 13) were grade 2, and 1.4% (n = 6) were grade 3. No grade 4 or 5 events were observed. Twenty-six of 63 RICE (41.3%) had resolved at the latest follow-up. The median onset after PBT and duration of RICE in patients in whom the lesions resolved were 11.8 and 9.0 months, respectively. On multivariable analysis, D1%CNS > 57.6 Gy RBE, previous in-field radiation, and diabetes mellitus were identified as significant risk factors for RICE development. Previous radiation was the only factor influencing the risk of symptomatic RICE. After PBT, general HRQoL parameters were not compromised. In a matched cohort analysis of 54/50 patients with and without RICE, no differences in global health score or functional and symptom scales were seen. CONCLUSIONS: The overall incidence of clinically relevant RICE after PBT is very low and has no significant negative effect on long-term patient QoL.

Simultaneous Dry and Gel-Based High-Density Electroencephalography Recordings.

Evaluations of new dry, high-density EEG caps have only been performed so far with serial measurements and not with simultaneous (parallel) measurements. For a first comparison of gel-based and dry electrode performance in simultaneous high-density EEG measurements, we developed a new EEG cap comprising 64 gel-based and 64 dry electrodes and performed simultaneous measurements on ten volunteers. We analyzed electrode-skin impedances, resting state EEG, triggered eye blinks, and visual evoked potentials (VEPs). To overcome the issue of different electrode positions in the comparison of simultaneous measurements, we performed spatial frequency analysis of the simultaneously measured EEGs using spatial harmonic analysis (SPHARA). The impedances were 516 ± 429 kOhm (mean ± std) for the dry electrodes and 14 ± 8 kOhm for the gel-based electrodes. For the dry EEG electrodes, we obtained a channel reliability of 77%. We observed no differences between dry and gel-based recordings for the alpha peak frequency and the alpha power amplitude, as well as for the VEP peak amplitudes and latencies. For the VEP, the RMSD and the correlation coefficient between the gel-based and dry recordings were 1.7 ± 0.7 µV and 0.97 ± 0.03, respectively. We observed no differences in the cumulative power distributions of the spatial frequency components for the N75 and P100 VEP peaks. The differences for the N145 VEP peak were attributed to the different noise characteristics of gel-based and dry recordings. In conclusion, we provide evidence for the equivalence of simultaneous dry and gel-based high-density EEG measurements.

Spatiotemporal phase slip patterns for visual evoked potentials, covert object naming tasks, and insight moments extracted from 256 channel EEG recordings.

Phase slips arise from state transitions of the coordinated activity of cortical neurons which can be extracted from the EEG data. The phase slip rates (PSRs) were studied from the high-density (256 channel) EEG data, sampled at 16.384 kHz, of five adult subjects during covert visual object naming tasks. Artifact-free data from 29 trials were averaged for each subject. The analysis was performed to look for phase slips in the theta (4-7 Hz), alpha (7-12 Hz), beta (12-30 Hz), and low gamma (30-49 Hz) bands. The phase was calculated with the Hilbert transform, then unwrapped and detrended to look for phase slip rates in a 1.0 ms wide stepping window with a step size of 0.06 ms. The spatiotemporal plots of the PSRs were made by using a montage layout of 256 equidistant electrode positions. The spatiotemporal profiles of EEG and PSRs during the stimulus and the first second of the post-stimulus period were examined in detail to study the visual evoked potentials and different stages of visual object recognition in the visual, language, and memory areas. It was found that the activity areas of PSRs were different as compared with EEG activity areas during the stimulus and post-stimulus periods. Different stages of the insight moments during the covert object naming tasks were examined from PSRs and it was found to be about 512 ± 21 ms for the 'Eureka' moment. Overall, these results indicate that information about the cortical phase transitions can be derived from the measured EEG data and can be used in a complementary fashion to study the cognitive behavior of the brain.

SPHARA--a generalized spatial Fourier analysis for multi-sensor systems with non-uniformly arranged sensors: application to EEG.

Important requirements for the analysis of multichannel EEG data are efficient techniques for signal enhancement, signal decomposition, feature extraction, and dimensionality reduction. We propose a new approach for spatial harmonic analysis (SPHARA) that extends the classical spatial Fourier analysis to EEG sensors positioned non-uniformly on the surface of the head. The proposed method is based on the eigenanalysis of the discrete Laplace-Beltrami operator defined on a triangular mesh. We present several ways to discretize the continuous Laplace-Beltrami operator and compare the properties of the resulting basis functions computed using these discretization methods. We apply SPHARA to somatosensory evoked potential data from eleven volunteers and demonstrate the ability of the method for spatial data decomposition, dimensionality reduction and noise suppression. When employing SPHARA for dimensionality reduction, a significantly more compact representation can be achieved using the FEM approach, compared to the other discretization methods. Using FEM, to recover 95% and 99% of the total energy of the EEG data, on average only 35% and 58% of the coefficients are necessary. The capability of SPHARA for noise suppression is shown using artificial data. We conclude that SPHARA can be used for spatial harmonic analysis of multi-sensor data at arbitrary positions and can be utilized in a variety of other applications.

Analysis of induced components in electroencephalograms using a multiple correlation method.

BACKGROUND: Evoked and induced activities are two typical components in the EEG and MEG time series after a stimulation. While evoked activity is phase-locked to the stimulus, induced activity is not. Present analysis methods are able to detect non-phase-locked parts of the signal, however, they do not improve the signal-to-noise ratio (SNR) of these signal components. RESULTS: We present a new method for estimating induced activation in EEG multi-trial data sets. It is based on the multiple correlation of single trials. Our method not only detects induced components within the EEG signal, it also improves their SNR. The method is successfully tested with artificial data sets. Application to real data is exemplified using EEG data recorded in a photic driving experiment. CONCLUSION: We show that the SNR of the induced activity is enhanced by our method, and the method found longer lasting induced activity after the end of stimulation compared with a conventional method.