BACKGROUND: Paclitaxel chemotherapy frequently induces dose-limiting sensory axonal polyneuropathy. Given that sensory symptoms are challenging to assess objectively in clinical practice, an easily accessible biomarker for chemotherapy-induced polyneuropathy (CIPN) holds the potential to improve early diagnosis. Here, we describe neurofilament light chain (NFL), a marker for neuroaxonal damage, as a translational surrogate marker for CIPN. METHODS: NFL concentrations were measured in an in vitro model of CIPN, exposing induced pluripotent stem cell–derived sensory neurons (iPSC-DSNs) to paclitaxel. Patients with breast or ovarian cancer undergoing paclitaxel chemotherapy, breast cancer control patients without chemotherapy, and healthy controls were recruited in a cohort study and examined before chemotherapy (V1) and after 28 weeks (V2, after chemotherapy). CIPN was assessed by the validated Total Neuropathy Score reduced (TNSr), which combines patient-reported symptoms with data from clinical examinations. Serum NFL (NFL _s ) concentrations were measured at both visits with single-molecule array technology. RESULTS: NFL was released from iPSC-DSNs upon paclitaxel incubation in a dose- and time-dependent manner and was inversely correlated with iPSC-DSN viability. NFL _s strongly increased in paclitaxel-treated patients with CIPN, but not in patients receiving chemotherapy without CIPN or controls, resulting in an 86% sensitivity and 87% specificity. An NFL _s increase of +36 pg/mL from baseline was associated with a predicted CIPN probability of more than 0.5. CONCLUSION: NFL _s was correlated with CIPN development and severity, which may guide neurotoxic chemotherapy in the future. TRIAL REGISTRATION: ClinicalTrials.gov NCT02753036. FUNDING: Deutsche Forschungsgemeinschaft (EXC 257 NeuroCure), BMBF (Center for Stroke Research Berlin, 01 EO 0801), Animalfree Research, EU Horizon 2020 Innovative Medicines Initiative 2 Joint Undertaking (TransBioLine, 821283), Charité 3R — Replace — Reduce — Refine.

Only very few viruses of Oomycetes have been studied in detail. Isometric virions were found in different isolates of the oomycete Plasmopara halstedii, the downy mildew pathogen of sunflower. However, complete nucleotide sequences and data on the genome organization were lacking.

Aim: Novel bifunctional VEGF-A neutralizing therapies are being developed for the treatment of retinal vascular diseases such as age-related macular degeneration and diabetic retinopathy. In develo...

Procalcitonin (PCT) is well established as a highly specific biomarker for the detection of bacterial infections and sepsis. However, the currently available diagnostic tests are not able to detect very low or very early increases of PCT or even baseline levels in healthy individuals or patients with non-bacterial infections. In order to be able to detect these very low concentrations of PCT, a sandwich immunoassay was developed using high sensitivity Single Molecule Array technology (Simoa). The assay was thoroughly validated and applied to analyze human cerebrospinal fluid (CSF) and serum samples from patients with bacterial or viral meningitis as well as CSF, serum, and K2 EDTA plasma from healthy control subjects. A 50-fold increase in sensitivity compared to the current gold standard assays was achieved, which was sensitive enough for the detection of baseline PCT levels. Both serum and CSF showed significantly elevated PCT levels in patients with bacterial meningitis compared to patients with viral meningitis and the healthy control group. Procalcitonin concentration levels for patients with viral meningitis and the control group could be measured, but were not significantly different. The determination of PCT in the low pg·mL⁻¹ range could help to improve the monitoring of bacterial infectious diseases, as PCT level changes could be detected earlier.

Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation.

In this study, we measured serum interferon (IFN) levels and activity in patients with sarcoidosis and tuberculosis (TB) with and without uveitis. We aimed to understand the role of IFN in the pathophysiology of both conditions and explore its potential as a discriminating marker for these clinically similar diseases. Sera from an Indonesian TB and a Dutch sarcoidosis cohort were used in the analysis. IFNα2 and IFNγ concentrations were measured using Simoa® and Luminex assays, respectively. Serum IFN activity was assessed by incubating THP-1 cells with patient serum and measuring IFN-stimulated gene transcription using qPCR. Anti-IFNα2 and IFNγ autoantibodies were detected via Luminex assay and tested for neutralizing capacity using a flow cytometry-based signal transducer and activator of transcription (STAT) 1 phosphorylation inhibition assay. IFNα2 was detected in 74 % and 64 % of patients with sarcoidosis and pulmonary TB, respectively, while IFNγ was found in 78 % and 23 % of patients with sarcoidosis and TB, respectively. For uveitis cases specifically, IFNα2 was detected in 85 % of sarcoid uveitis (SU) and 33 % of tubercular uveitis (TBU) cases. Similarly, IFNγ was detected in 69 % of SU and 17 % of TBU cases. IFNγ serum concentrations were higher in sarcoidosis than that in TB patients (p < 0.0001). Focusing on patients with uveitis, SU showed increased IFNα2 (p = 0.004) and IFNγ (p < 0.002) serum concentrations compared to that in TBU. Notably, TBU displayed significantly reduced IFNα2 concentrations compared to that in healthy controls (p = 0.006). These results align with the increased interferon stimulated gene (ISG) transcriptional upregulation observed in THP-1 cells stimulated with serum from patients with sarcoidosis. Elevated levels of non-neutralizing anti-IFN autoantibodies were observed in patients with TB; however, these levels were similar to those observed in geographically matched healthy Indonesian controls. Our results suggest decreased serum levels and activity of type I and II IFN in TB compared to those in sarcoidosis. This is indicative of distinct pathophysiological processes in these highly clinically similar diseases. We propose that the assessment of serum IFN levels and IFN activity has the potential to distinguish between sarcoidosis/SU and TB/TBU.