Targeting Neuropilin-1 with Nanobodies Reduces Colorectal Carcinoma Development.

Neuropilin-1 (NRP-1) is a co-receptor for semaphorins and vascular endothelial growth factor (VEGF) family members that can be expressed on cancer cells and tumor-infiltrating myeloid, endothelial and lymphoid cells. It has been linked to a tumor-promoting environment upon interaction with semaphorin 3A (Sema3A). Nanobodies (Nbs) targeting NRP-1 were generated for their potential to hamper the NRP-1/Sema3A interaction and their impact on colorectal carcinoma (CRC) development was evaluated in vivo through the generation of anti-NRP-1-producing CRC cells. We observed that tumor growth was significantly delayed and survival prolonged when the anti-NRP-1 Nbs were produced in vivo. We further analyzed the tumor microenvironment and observed that the pro-inflammatory MHC-IIhigh/trophic MHC-IIlow macrophage ratio was increased in tumors that produce anti-NRP-1 Nbs. This finding was corroborated by an increase in the expression of genes associated with MHC-IIhigh macrophages and a decrease in the expression of MHC-IIlow macrophage-associated genes in the macrophage pool sorted from anti-NRP-1 Nb-producing tumors. Moreover, we observed a significantly higher percentage of tumor-associated antigen-specific CD8+ T cells in tumors producing anti-NRP-1 Nbs. These data demonstrate that an intratumoral expression of NRP-1/Sema3A blocking biologicals increases anti-tumor immunity.

Stress Assessment by Combining Neurophysiological Signals and Radio Communications of Air Traffic Controllers.

Air Traffic Control (ATC) has been classified as the fourth most stressful job. In this regard, sixteen controllers were asked to perform ecological ATC simulation during which behavioral (Radio Communications with pilots - RCs), subjective (stress perception) and neurophysiological signals (brain activity and skin conductance - SC) were collected. All the considered parameters reported significant changes under high stress conditions. In particular, the theta, alpha, and beta brain rhythms increased significantly (all p<0.05) all over the brain areas, and both the SC components exhibited higher values (p<0.01). Additionally, the number of speech under high stress decreased significantly (p<10-4) while both the mean and median value of the F0 component of the RC increased (p<0.01). The results can be employed to objectively measure and track the controller's stress level while dealing with ATC activities to better tailoring the workshift and maintaining high safety levels.

A multimodal and signals fusion approach for assessing the impact of stressful events on Air Traffic Controllers.

Stress is a word used to describe human reactions to emotionally, cognitively and physically challenging experiences. A hallmark of the stress response is the activation of the autonomic nervous system, resulting in the "fight-freeze-flight" response to a threat from a dangerous situation. Consequently, the capability to objectively assess and track a controller's stress level while dealing with air traffic control (ATC) activities would make it possible to better tailor the work shift and maintain high safety levels, as well as to preserve the operator's health. In this regard, sixteen controllers were asked to perform a realistic air traffic management (ATM) simulation during which subjective data (i.e. stress perception) and neurophysiological data (i.e. brain activity, heart rate, and galvanic skin response) were collected with the aim of accurately characterising the controller's stress level experienced in the various experimental conditions. In addition, external supervisors regularly evaluated the controllers in terms of manifested stress, safety, and efficiency throughout the ATM scenario. The results demonstrated 1) how the stressful events caused both supervisors and controllers to underestimate the experienced stress level, 2) the advantage of taking into account both cognitive and hormonal processes in order to define a reliable stress index, and 3) the importance of the points in time at which stress is measured owing to the potential transient effect once the stressful events have ceased.

Toward a cooperation index based on EEG-workload causality: preliminary findings on aerospace-like tasks.

According to Human-System Integration analyses, cooperation between humans is one of the most relevant factors in many of today's human activities: do not take it into account in models of working environments is highly farfetched. Although the Human Factor aspects have obtained much benefit from the use of neurophysiological signals to estimate human-machine interaction, very few are the indications about neurophysiological analysis of human cooperation deviating from typical laboratory tasks. Among these, some evidence showed that there is a relationship between the mental workload experienced by the subjects cooperating and some characteristics of the brain network obtained through multi-subjects connectivity analysis. Accordingly, this work aimed to identify common dynamics in time series that describe the EEG-based mental workload of cooperating subjects and to exploit this information to create an index of cooperation. In order to answer the question whether a causality between the workload values of the two subjects can be in some way discerned and related to the cooperation required by the task, Granger's causality test has been performed. This method was applied to two different tasks simulating features of the aerospace domain. The results showed that the causality test was statistically significant for the most collaborating couple. In addition, causality values are modulated by the presence of real couples compared to fake couples. The extension of the experimental sample could open up the possibility for the development of an objective and neurophysiological signals-based cooperation index.

Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies.

Cancer cell dependence on activated oncogenes is therapeutically targeted, but acquired resistance is virtually unavoidable. Here we show that the treatment of addicted melanoma cells with BRAF inhibitors, and of breast cancer cells with HER2-targeted drugs, led to an adaptive rise in neuropilin-1 (NRP1) expression, which is crucial for the onset of acquired resistance to therapy. Moreover, NRP1 levels dictated the efficacy of MET oncogene inhibitors in addicted stomach and lung carcinoma cells. Mechanistically, NRP1 induced a JNK-dependent signaling cascade leading to the upregulation of alternative effector kinases EGFR or IGF1R, which in turn sustained cancer cell growth and mediated acquired resistance to BRAF, HER2, or MET inhibitors. Notably, the combination with NRP1-interfering molecules improved the efficacy of oncogene-targeted drugs and prevented or even reversed the onset of resistance in cancer cells and tumor models. Our study provides the rationale for targeting the NRP1-dependent upregulation of tyrosine kinases, which are responsible for loss of responsiveness to oncogene-targeted therapies.

Beyond the M-CSF receptor - novel therapeutic targets in tumor-associated macrophages.

Tumor-associated macrophages (TAM) are by now established as important regulators of tumor progression by impacting on tumor immunity, angiogenesis, and metastasis. Hence, a multitude of approaches are currently pursued to intervene with TAM's protumor activities, the most advanced of which being a blockade of macrophage-colony stimulating factor (M-CSF)/M-CSF receptor (M-CSFR) signaling. M-CSFR signaling largely impacts on the differentiation of macrophages, including TAM, and hence strongly influences the numbers of these cells in tumors. However, a repolarization of TAM toward a more antitumor phenotype may be more elegant and may yield stronger effects on tumor growth. In this respect, several aspects of TAM behavior could be altered, such as their intratumoral localization, metabolism and regulatory pathways. Intervention strategies could include the use of small molecules but also new generations of biologicals which may complement the current success of immune checkpoint blockers. This review highlights current work on the search for new therapeutic targets in TAM.

EEG-Based Cognitive Control Behaviour Assessment: an Ecological study with Professional Air Traffic Controllers.

Several models defining different types of cognitive human behaviour are available. For this work, we have selected the Skill, Rule and Knowledge (SRK) model proposed by Rasmussen in 1983. This model is currently broadly used in safety critical domains, such as the aviation. Nowadays, there are no tools able to assess at which level of cognitive control the operator is dealing with the considered task, that is if he/she is performing the task as an automated routine (skill level), as procedures-based activity (rule level), or as a problem-solving process (knowledge level). Several studies tried to model the SRK behaviours from a Human Factor perspective. Despite such studies, there are no evidences in which such behaviours have been evaluated from a neurophysiological point of view, for example, by considering brain activity variations across the different SRK levels. Therefore, the proposed study aimed to investigate the use of neurophysiological signals to assess the cognitive control behaviours accordingly to the SRK taxonomy. The results of the study, performed on 37 professional Air Traffic Controllers, demonstrated that specific brain features could characterize and discriminate the different SRK levels, therefore enabling an objective assessment of the degree of cognitive control behaviours in realistic settings.

Human Factors and Neurophysiological Metrics in Air Traffic Control: A Critical Review.

This paper provides a focused and organized review of the research progress on neurophysiological indicators, also called "neurometrics," to show how they can effectively address some of the most important human factors (HFs) needs in the air traffic management (ATM) field. In order to better understand and highlight available opportunities of such neuroscientific applications, state of the art on the most involved HFs and related cognitive processes (e.g., mental workload and cognitive training) are presented together with examples of possible applications in current and future ATM scenarios. Furthermore, this paper will discuss the potential enhancements that further research and development activities could bring to the efficiency and safety of the ATM service.

Adaptive Automation Triggered by EEG-Based Mental Workload Index: A Passive Brain-Computer Interface Application in Realistic Air Traffic Control Environment.

Adaptive Automation (AA) is a promising approach to keep the task workload demand within appropriate levels in order to avoid both the under- and over-load conditions, hence enhancing the overall performance and safety of the human-machine system. The main issue on the use of AA is how to trigger the AA solutions without affecting the operative task. In this regard, passive Brain-Computer Interface (pBCI) systems are a good candidate to activate automation, since they are able to gather information about the covert behavior (e.g., mental workload) of a subject by analyzing its neurophysiological signals (i.e., brain activity), and without interfering with the ongoing operational activity. We proposed a pBCI system able to trigger AA solutions integrated in a realistic Air Traffic Management (ATM) research simulator developed and hosted at ENAC (École Nationale de l'Aviation Civile of Toulouse, France). Twelve Air Traffic Controller (ATCO) students have been involved in the experiment and they have been asked to perform ATM scenarios with and without the support of the AA solutions. Results demonstrated the effectiveness of the proposed pBCI system, since it enabled the AA mostly during the high-demanding conditions (i.e., overload situations) inducing a reduction of the mental workload under which the ATCOs were operating. On the contrary, as desired, the AA was not activated when workload level was under the threshold, to prevent too low demanding conditions that could bring the operator's workload level toward potentially dangerous conditions of underload.

Avionic technology testing by using a cognitive neurometric index: A study with professional helicopter pilots.

In this study, we investigated the possibility to evaluate the impact of different avionic technologies on the mental workload of helicopter's pilots by measuring their brain activity with the EEG during a series of simulated missions carried out at AgustaWestland facilities in Yeovil (UK). The tested avionic technologies were: i) Head-Up Display (HUD); ii) Head-Mounted Display (HMD); iii) Full Conformal symbology (FC); iv) Flight Guidance (FG) symbology; v) Synthetic Vision System (SVS); and vi) Radar Obstacles (RO) detection system. It has been already demonstrated that in cognitive tasks, when the cerebral workload increases the EEG power spectral density (PSD) in theta band over frontal areas increases, and the EEG PSD in alpha band decreases over parietal areas. A mental workload index (MWL) has been here defined as the ratio between the frontal theta and parietal alpha EEG PSD values. Such index has been used for testing and comparing the different avionic technologies. Results suggested that the HUD provided a significant (p<;.05) workload reduction across all the flight scenarios with respect to the other technologies. In addition, the simultaneous use of FC and FG technologies (FC+FG) produced a significant decrement of the workload (p<;.01) with respect to the use of only the FC. Moreover, the use of the SVS technology provided on Head Down Display (HDD) with the simultaneous use of FC+FG and the RO seemed to produce a lower cerebral workload when compared with the use of only the FC. Interestingly, the workload estimation by means of subjective measures, provided by pilots through a NASA-TLX questionnaire, did not provide any significant differences among the different flight scenarios. These results suggested that the proposed MWL cognitive neurometrics could be used as a reliable measure of the user's mental workload, being a valid indicator for the comparison and the test of different avionic technologies.

STAT of the union: dynamics of distinct tumor-associated macrophage subsets governed by STAT1.

The tumor stroma has long been ignored as therapeutic target, but it has become clear that several stromal cell types play a nonredundant role during tumor progression. In particular, macrophages possess the capacity to stimulate tumor growth and metastasis via multiple mechanisms. In this issue of the European Journal of Immunology, a study by Tymoszuk et al. Eur. J. Immunol. 2014. 44: 2247-2262 demonstrates that both monocyte recruitment and local macrophage proliferation determines the tumor-associated macrophage (TAM) pool size in HER2/Neu-driven mammary carcinomas. These tumors contain two main TAM subsets--MHC class II (MHC-II)(lo) F4/80(hi) and MHC-II(hi) F4/80(lo)--similar to what was observed in other tumor models. Interestingly, only the MHC-II(lo) F4/80(hi) subset is largely absent in a STAT1-deficient background. STAT1 induces the expression of CSF-1, which in turn drives TAM proliferation and possibly also the M2 gene signature of MHC-II(lo) F4/80(hi) TAM. Conversely, STAT1 deficiency upregulates M2 gene expression in MHC-II(hi) F4/80(lo) TAM, demonstrating that both TAM subsets are differentially regulated, probably as a consequence of their distinct intratumoral localization. In this Commentary, we place these findings in the context of current knowledge and propose new avenues for future research.