A central and unique aspect of high-grade serous ovarian carcinoma (HGSC) is the extensive transcoelomic spreading of tumor cell via the peritoneal fluid or malignant ascites. We and others ...identified tumor-associated macrophages (TAM) in the ascites as promoters of metastasis-associated processes like extracellular matrix (ECM) remodeling, tumor cell migration, adhesion, and invasion. The precise mechanisms and mediators involved in these functions of TAM are, however, largely unknown. We observed that HGSC migration is promoted by soluble mediators from ascites-derived TAM, which can be emulated by conditioned medium from monocyte-derived macrophages (MDM) differentiated in ascites to TAM-like asc-MDM. A similar effect was observed with IL-10-induced alternatively activated m2c-MDM but not with LPS/IFNγ-induced inflammatory m1-MDM. These observations provided the basis for deconvolution of the complex TAM secretome by performing comparative secretome analysis of matched triplets of different MDM phenotypes with different pro-migratory properties (asc-MDM, m2c-MDM, m1-MDM). Mass spectrometric analysis identified an overlapping set of nine proteins secreted by both asc-MDM and m2c-MDM, but not by m1-MDM. Of these, three proteins, i.e., transforming growth factor beta-induced (TGFBI) protein, tenascin C (TNC), and fibronectin (FN1), have been associated with migration-related functions. Intriguingly, increased ascites concentrations of TGFBI, TNC, and fibronectin were associated with short progression-free survival. Furthermore, transcriptome and secretome analyses point to TAM as major producers of these proteins, further supporting an essential role for TAM in promoting HGSC progression. Consistent with this hypothesis, we were able to demonstrate that the migration-inducing potential of asc-MDM and m2c-MDM secretomes is inhibited, at least partially, by neutralizing antibodies against TGFBI and TNC or siRNA-mediated silencing of TGFBI expression. In conclusion, the present study provides the first experimental evidence that TAM-derived TGFBI and TNC in ascites promote HGSC progression.
Perceptual attunement to one's native language results in language-specific processing of speech sounds. This includes stress cues, instantiated by differences in intensity, pitch, and duration. The ...present study investigates the effects of linguistic experience on the perception of these cues by studying the Iambic-Trochaic Law (ITL), which states that listeners group sounds trochaically (strong-weak) if the sounds vary in loudness or pitch and iambically (weak-strong) if they vary in duration. Participants were native listeners either of French or German; this comparison was chosen because French adults have been shown to be less sensitive than speakers of German and other languages to word-level stress, which is communicated by variation in cues such as intensity, fundamental frequency (F0), or duration. In experiment 1, participants listened to sequences of co-articulated syllables varying in either intensity or duration. The German participants were more consistent in their grouping than the French for both cues. Experiment 2 was identical to experiment 1 except that intensity variation was replaced by pitch variation. German participants again showed more consistency for both cues, and French participants showed especially inconsistent grouping for the pitch-varied sequences. These experiments show that the perception of linguistic rhythm is strongly influenced by linguistic experience.
Survival of ovarian carcinoma is associated with the abundance of immunosuppressed CD163highCD206high tumor‐associated macrophages (TAMs) and high levels of arachidonic acid (AA) in the tumor ...microenvironment. Here, we show that both associations are functionally linked. Transcriptional profiling revealed that high CD163 and CD206/MRC1 expression in TAMs is strongly associated with an inhibition of cytokine‐triggered signaling, mirrored by an impaired transcriptional response to interferons and IL‐6 in monocyte‐derived macrophages by AA. This inhibition of pro‐inflammatory signaling is caused by dysfunctions of the cognate receptors, indicated by the inhibition of JAK1, JAK2, STAT1, and STAT3 phosphorylation, and by the displacement of the interferon receptor IFNAR1, STAT1 and other immune‐regulatory proteins from lipid rafts. AA exposure led to a dramatic accumulation of free AA in lipid rafts, which appears to be mechanistically crucial, as the inhibition of its incorporation into phospholipids did not affect the AA‐mediated interference with STAT1 phosphorylation. Inhibition of interferon‐triggered STAT1 phosphorylation by AA was reversed by water‐soluble cholesterol, known to prevent the perturbation of lipid raft structure by AA. These findings suggest that the pharmacologic restoration of lipid raft functions in TAMs may contribute to the development new therapeutic approaches.
This study shows that the clinically adverse abundance of immunocompromised macrophages and arachidonic acid (AA) in the ovarian carcinoma microenvironment (TME) are functionally linked. AA impairs transcriptional signalling via JAK/STAT‐dependent cytokine receptors by counteracting compartmentalization of receptor and STAT proteins into lipid rafts. Inhibition of STAT signalling is reversible by protecting lipid raft structure with water‐soluble cholesterol, pointing to potential therapeutic applications.
Tumors frequently exploit homeostatic mechanisms that suppress expression of IL-12, a central mediator of inflammatory and anti-tumor responses. The p40 subunit of the IL-12 heterodimer, encoded by
, ...is limiting for these functions. Ovarian carcinoma patients frequently produce ascites which exerts immunosuppression by means of soluble factors. The NFκB pathway is necessary for transcription of
, which is not expressed in macrophages freshly isolated from ascites. This raises the possibility that ascites prevents
expression by perturbing NFκB binding to chromatin. Here, we show that ascites-mediated suppression of
induction by LPS plus IFNγ in primary human macrophages is rapid, and that suppression can be reversible after ascites withdrawal. Nuclear translocation of the NFκB transcription factors
-REL and p65 was strongly reduced by ascites. Surprisingly, however, their binding to the
locus and to
, a second NFκB target gene, was unaltered, and the induction of
transcription was not suppressed by ascites. These findings indicate that, despite its reduced nuclear translocation, NFκB function is not generally impaired by ascites, suggesting that ascites-borne signals target additional pathways to suppress
induction. Consistent with these data, IL-10, a clinically relevant constituent of ascites and negative regulator of NFκB translocation, only partially recapitulated
suppression by ascites. Finally, restoration of a defective IL-12 response by appropriate culture conditions was observed only in macrophages from a subset of donors, which may have important implications for the understanding of patient-specific immune responses.
This study provides a novel approach for testing the universality of perceptual biases by looking at speech processing in simultaneous bilingual adults learning two languages that support the ...maintenance of this bias to different degrees. Specifically, we investigated the Iambic/Trochaic Law, an assumed universal grouping bias, in simultaneous French–German bilinguals, presenting them with streams of syllables varying in intensity, duration or neither and asking them whether they perceived them as strong-weak or weak-strong groupings. Results showed robust, consistent grouping preferences. A comparison to monolinguals from previous studies revealed that they pattern with German-speaking monolinguals, and differ from French-speaking monolinguals. The distribution of simultaneous bilinguals' individual performance was best explained by a model fitting a unimodal (not bimodal) distribution, failing to support two subgroups of language dominance. Moreover, neither language experience nor language context predicted their performance. These findings suggest a special role for universal biases in simultaneous bilinguals.
Rhythm perception is assumed to be guided by a domain-general auditory principle, the Iambic/Trochaic Law, stating that sounds varying in intensity are grouped as strong-weak, and sounds varying in ...duration are grouped as weak-strong. Recently, Bhatara et al. (2013) showed that rhythmic grouping is influenced by native language experience, French listeners having weaker grouping preferences than German listeners. This study explores whether L2 knowledge and musical experience also affect rhythmic grouping. In a grouping task, French late learners of German listened to sequences of coarticulated syllables varying in either intensity or duration. Data on their language and musical experience were obtained by a questionnaire. Mixed-effect model comparisons showed influences of musical experience as well as L2 input quality and quantity on grouping preferences. These results imply that adult French listeners’ sensitivity to rhythm can be enhanced through L2 and musical experience.
Arachidonic acid (AA) is a polyunsaturated fatty acid present at high concentrations in the ovarian cancer (OC) microenvironment and associated with a poor clinical outcome. In the present study, we ...have unraveled a potential link between AA and macrophage functions.
AA-triggered signal transduction was studied in primary monocyte-derived macrophages (MDMs) by phosphoproteomics, transcriptional profiling, measurement of intracellular Ca
accumulation and reactive oxygen species production in conjunction with bioinformatic analyses. Functional effects were investigated by actin filament staining, quantification of macropinocytosis and analysis of extracellular vesicle release.
We identified the ASK1 - p38δ/α (MAPK13/14) axis as a central constituent of signal transduction pathways triggered by non-metabolized AA. This pathway was induced by the Ca
-triggered activation of calmodulin kinase II, and to a minor extent by ROS generation in a subset of donors. Activated p38 in turn was linked to a transcriptional stress response associated with a poor relapse-free survival. Consistent with the phosphorylation of the p38 substrate HSP27 and the (de)phosphorylation of multiple regulators of Rho family GTPases, AA impaired actin filament organization and inhibited actin-driven macropinocytosis. AA also affected the phosphorylation of proteins regulating vesicle biogenesis, and consistently, AA enhanced the release of tetraspanin-containing exosome-like vesicles. Finally, we identified phospholipase A
group 2A (PLA2G2A) as the clinically most relevant enzyme producing extracellular AA, providing further potentially theranostic options.
Our results suggest that AA contributes to an unfavorable clinical outcome of OC by impacting the phenotype of tumor-associated macrophages. Besides critical AA-regulated signal transduction proteins identified in the present study, PLA2G2A might represent a potential prognostic tool and therapeutic target to interfere with OC progression.
In this article, a methodology for fine scale modeling of large scale linear elastic structures is proposed, which combines the variational multiscale method, domain decomposition and model order ...reduction. The influence of the fine scale on the coarse scale is modeled by the use of an additive split of the displacement field, addressing applications without a clear scale separation. Local reduced spaces are constructed by solving an oversampling problem with random boundary conditions. Herein, we inform the boundary conditions by a global reduced problem and compare our approach using physically meaningful correlated samples with existing approaches using uncorrelated samples. The local spaces are designed such that the local contribution of each subdomain can be coupled in a conforming way, which also preserves the sparsity pattern of standard finite element assembly procedures. Several numerical experiments show the accuracy and efficiency of the method, as well as its potential to reduce the size of the local spaces and the number of training samples compared to the uncorrelated sampling.
Thermal imaging can be used for the non-invasive detection of blood vessels of the skin. However, mapping the results to the patient currently lacks user-friendliness. Augmented reality may provide a ...useful tool to superimpose thermal information on the patient.
A system to support planning in reconstructive surgery using a thermal camera was designed. The obtained information was superimposed on the physical object using a Microsoft HoloLens. An RGB, depth, and thermal camera were combined to capture a scene of different modalities and reconstruct a virtual scene in real time. To register the different cameras and the AR device, an active calibration target was developed and evaluated. A Vuforia marker was used to register the hologram in the virtual space. The accuracy of the projected hologram was evaluated in a laboratory setting with participants by measuring the error between the physical object and the hologram.
The AR-based system was evaluated by 21 participants in a laboratory setting. The mean projection error is 10.3 ± 9.4 mm. The system is able to stream a three-dimensional scene with augmented thermal information in real time at 5 frames per second. The active calibration target can be used independently of the environment.
The calibration target provides an easy-to-use method for the registration of cameras capturing the visible to long-infrared spectral range. The inside-out tracking of the HoloLens in combination with a Vuforia marker is not accurate enough for the intended clinical use.
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