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Land-based coastal high-frequency (HF) radar systems provide operational measurements of coastal surface currents (within 1–3 m depth) with high spatial (300 m–10 km) and temporal ( ≤ 1 h) sampling resolutions, while the near-continuous altimetry missions provide information, from 1993 until today, on geostrophic currents in the global ocean with typical along-track and temporal sampling resolutions of > 7 km and > 9 days, respectively. During the last years, the altimetry community has made a step forward in improving these data in the coastal area, where the data present lower quality than in the open ocean. The combination of HF radar and altimetry measurements arises as a promising strategy to improve the continuous monitoring of the coastal area (e.g. by expanding the measurements made by HF radars to adjacent areas covered by the altimetry or by validating/confirming improvements brought by specific coastal algorithms or new altimeter missions). A first step towards this combination is the comparison of both data sets in overlapping areas.In this study, a HF radar system and two Jason-2 satellite altimetry products with different processing are compared over the period from 1 January 2009 to 24 July 2015. The results provide an evaluation of the performance of different coastal altimetry data sets within the study area and a better understanding of the ocean variability contained in the HF radar and altimetry data sets. Both observing systems detect the main mesoscale processes within the study area (the Iberian Poleward Current and mesoscale eddies), and the highest correlations between radar and altimetry (up to 0.64) occur in the slope where the Iberian Poleward Current represents a significant part of the variability in the circulation. Besides, the use of an Ekman model, to add the wind-induced current component to the altimetry-derived geostrophic currents, increases the agreement between both data sets (increasing the correlation by around 10 %).

The European MyOcean project (http://www.myocean.eu.org) provides observations of the ocean dynamic topography from altimeter measurements. Three specific indicators have been developed, based on altimeter data only, in order to monitor the ocean state. The first ocean indicator observes the positive and negative phases of the ENSO events in the tropical Pacific, the El Niño/La Niña events, since 1992. The second ocean indicator tracks the contracted or extended state of the Kuroshio Extension. The last ocean indicator is dedicated to the Ionian Basin in the Mediterranean Sea and permits separation of "zonal-cyclonic" state (1998–2005 and since 2011 up to now) from the "anticyclonic" state (1993–1996) usually discussed in the literature. In addition, it allows identifying a third state in which both the anticyclonic circulation around the northern part of the basin and the strong zonal Mid-Ionian Jet co-exist (2008–2010).

A large number of SLA observations at a high along track horizontal resolution are an important ingredient of the data assimilation in the Mediterranean Forecasting System (MFS). Recently, new higher-frequency SLA products have become available, and the atmospheric pressure forcing has been implemented in the numerical model used in the MFS data assimilation system. In a set of numerical experiments, we show that, in order to obtain the most accurate analyses, the ocean model should include the atmospheric pressure forcing and the observations should contain the atmospheric pressure signal. When the model is not forced by the atmospheric pressure, the high-frequency filtering of SLA observations, however, improves the quality of the SLA analyses. It is further shown by comparing the power density spectra of the model fields and observations that the model is able to extract the correct information from noisy observations even without their filtering during the pre-processing.

The impact of the assimilation of MyOcean sea level anomalies along-track data on the analyses of the Sicily Channel Regional Model was studied. The numerical model has a resolution of 1/32° degrees and is capable to reproduce mesoscale and sub-mesoscale features. The impact of the SLA assimilation is studied by comparing a simulation (SIM, which does not assimilate data) with an analysis (AN) assimilating SLA along-track multi-mission data produced in the framework of MyOcean project. The quality of the analysis was evaluated by computing RMSE of the misfits between analysis background and observations (sea level) before assimilation. A qualitative evaluation of the ability of the analyses to reproduce mesoscale structures is accomplished by comparing model results with ocean colour and SST satellite data, able to detect such features on the ocean surface. CTD profiles allowed to evaluate the impact of the SLA assimilation along the water column. We found a significant improvement for AN solution in terms of SLA RMSE with respect to SIM (the averaged RMSE of AN SLA misfits over 2 years is about 0.5 cm smaller than SIM). Comparison with CTD data shows a questionable improvement produced by the assimilation process in terms of vertical features: AN is better in temperature while for salinity it gets worse than SIM at the surface. This suggests that a better a-priori description of the vertical error covariances would be desirable. The qualitative comparison of simulation and analyses with synoptic satellite independent data proves that SLA assimilation allows to correctly reproduce some dynamical features (above all the circulation in the Ionian portion of the domain) and mesoscale structures otherwise misplaced or neglected by SIM. Such mesoscale changes also infer that the eddy momentum fluxes (i.e. Reynolds stresses) show major changes in the Ionian area. Changes in Reynolds stresses reflect a different pumping of eastward momentum from the eddy to the mean flow, in turn influencing transports through the channel.

Ammonia (NH3) is an important air pollutant which, as a precursor of fine particulate matter, raises public health concerns. This study analyzes 2.5 years of NH3 observations derived from ground-based (miniDOAS; differential optical absorption spectroscopy) and satellite (IASI; Infrared Atmospheric Sounding Interferometer) remote sensing instruments to quantify, for the first time, temporal variabilities (from interannual to diurnal) in NH3 concentrations in Paris. The IASI and miniDOAS datasets are found to be in relatively good agreement (R>0.70) when atmospheric NH3 concentrations are high and driven by regional agricultural activities. Over the investigated period (January 2020–June 2022), NH3 average concentrations in Paris measured by the miniDOAS and IASI are 2.23 µg m−3 and 7.10×1015 molec. cm−2, respectively, which are lower than or equivalent to those documented in other urban areas. The seasonal and monthly variabilities in NH3 concentrations in Paris are driven by sporadic agricultural emissions influenced by meteorological conditions, with NH3 concentrations in spring up to 2 times higher than in other seasons. The potential source contribution function (PSCF) reveals that the close (100–200 km) east and northeast regions of Paris constitute the most important potential emission source areas of NH3 in the megacity. Weekly cycles of NH3 derived from satellite and ground-based observations show different ammonia sources in Paris. In spring, agriculture has a major influence on ammonia concentrations, and, in the other seasons, multi-platform observations suggest that ammonia is also controlled by traffic-related emissions. In Paris, the diurnal cycle of NH3 concentrations is very similar to the one of NO2, with morning enhancements coincident with intensified road traffic. NH3 evening enhancements synchronous with rush hours are also monitored in winter and fall. NH3 concentrations measured during the weekends are consistently lower than NH3 concentrations measured during weekdays in summer and fall. This is further evidence of a significant traffic source of NH3 in Paris.

Introduction: Advanced cutaneous melanoma is a skin cancer characterized by a poor prognosis and high metastatic potential. During metastatic spread, melanoma cells often undergo dedifferentiation toward an invasive phenotype, resulting in reduced expression of microphthalmia-associated transcription factor (MITF)-dependent melanoma antigens and facilitating immune escape. Tumor Necrosis Factor (TNF) is known to be a key factor in melanoma dedifferentiation. Interestingly, accumulating evidence suggests that TNF may play a role in melanoma progression and resistance to immunotherapies. Additionally, TNF has been identified as a potent regulator of sphingolipid metabolism, which could contribute to melanoma aggressiveness and the process of melanoma dedifferentiation., Methods: We conducted RNA sequencing and mass spectrometry analyses to investigate TNF-induced dedifferentiation in two melanoma cell lines. In vitro experiments were performed to manipulate sphingolipid metabolism using genetic or pharmacologic alterations in combination with TNF treatment, aiming to elucidate the potential involvement of this metabolism in TNF-induced dedifferentiation. Lastly, to evaluate the clinical significance of our findings, we performed unsupervised analysis of plasma sphingolipid levels in 48 patients receiving treatment with immune checkpoint inhibitors, either alone or in combination with anti-TNF therapy., Results: Herein, we demonstrate that TNF-induced melanoma cell dedifferentiation is associated with a global modulation of sphingolipid metabolism. Specifically, TNF decreases the expression and activity of acid ceramidase (AC), encoded by the ASAH1 gene, while increasing the expression of glucosylceramide synthase (GCS), encoded by the UGCG gene. Remarkably, knockdown of AC alone via RNA interference is enough to induce melanoma cell dedifferentiation. Furthermore, treatment with Eliglustat, a GCS inhibitor, inhibits TNF-induced melanoma cell dedifferentiation. Lastly, analysis of plasma samples from patients treated with immune checkpoint inhibitors, with or without anti-TNF therapy, revealed significant predictive sphingolipids. Notably, the top 8 predictive sphingolipids, including glycosphingolipids, were associated with a poor response to immunotherapy., Discussion: Our study highlights that ceramide metabolism alterations are causally involved in TNF-induced melanoma cell dedifferentiation and suggests that the evolution of specific ceramide metabolites in plasma may be considered as predictive biomarkers of resistance to immunotherapy., Competing Interests: NM reports grants and personal fees from Bristol-Myers Squibb and MSD, and personal fees from Roche, Novartis, Pierre Fabre, Sanofi, Sun Pharma, and AbbVie outside the submitted work. VP reports grants from Pierre Fabre outside of the submitted work. BS reports grants and personal fees from Bristol-Myers Squibb outside the submitted work. J-PD reports being advisory board member for BMS, MSD, Pierre Fabre, Roche and Amgen, and received research grant from Amgen, Astra Zeneca, BMS, Genentech, MSD, Transgene outside the submitted work. BS, CD, MG, AM, TL, NM, J-PD, and NA-A declare a patent pending application number: EP22306318; filled in Sept 6, 2022. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dufau, Genais, Mucher, Jung, Garcia, Montfort, Tosolini, Clarke, Medin, Levade, Delord, Meyer, Pancaldi, Andrieu-Abadie and Ségui.)

Lipid amidases of therapeutic relevance include acid ceramidase (AC), N-acylethanolamine-hydrolyzing acid amidase, and fatty acid amide hydrolase (FAAH). Although fluorogenic substrates have been developed for the three enzymes and high-throughput methods for screening have been reported, a platform for the specific detection of these enzyme activities in intact cells is lacking. In this article, we report on the coumarinic 1-deoxydihydroceramide RBM1-151, a 1-deoxy derivative and vinilog of RBM14-C12, as a novel substrate of amidases. This compound is hydrolyzed by AC ( app K m  = 7.0 μM; app V max  = 99.3 nM/min), N-acylethanolamine-hydrolyzing acid amidase ( app K m  = 0.73 μM; app V max  = 0.24 nM/min), and FAAH ( app K m  = 3.6 μM; app V max  = 7.6 nM/min) but not by other ceramidases. We provide proof of concept that the use of RBM1-151 in combination with reported irreversible inhibitors of AC and FAAH allows the determination in parallel of the three amidase activities in single experiments in intact cells., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Dysregulation of lipid metabolism affects the behavior of cancer cells, but how this happens is not completely understood. Neutral sphingomyelinase 2 (nSMase2), encoded by SMPD3 , catalyzes the breakdown of sphingomyelin to produce the anti-oncometabolite ceramide. We found that this enzyme was often downregulated in human metastatic melanoma, likely contributing to immune escape. Overexpression of nSMase2 in mouse melanoma reduced tumor growth in syngeneic wild-type but not CD8-deficient mice. In wild-type mice, nSMase2-overexpressing tumors showed accumulation of both ceramide and CD8 + tumor-infiltrating lymphocytes, and this was associated with increased level of transcripts encoding IFNγ and CXCL9. Overexpressing the catalytically inactive nSMase2 failed to alter tumor growth, indicating that the deleterious effect nSMase2 has on melanoma growth depends on its enzymatic activity. In vitro , small extracellular vesicles from melanoma cells overexpressing wild-type nSMase2 augmented the expression of IL12, CXCL9, and CCL19 by bone marrow-derived dendritic cells, suggesting that melanoma nSMase2 triggers T helper 1 (Th1) polarization in the earliest stages of the immune response. Most importantly, overexpression of wild-type nSMase2 increased anti-PD-1 efficacy in murine models of melanoma and breast cancer, and this was associated with an enhanced Th1 response. Therefore, increasing SMPD3 expression in melanoma may serve as an original therapeutic strategy to potentiate Th1 polarization and CD8 + T-cell-dependent immune responses and overcome resistance to anti-PD-1., (©2021 American Association for Cancer Research.)

Purpose: TNF blockers can be used to manage gastrointestinal inflammatory side effects following nivolumab and/or ipilimumab treatment in patients with advanced melanoma. Our preclinical data showed that anti-TNF could promote the efficacy of immune checkpoint inhibitors., Patients and Methods: TICIMEL (NTC03293784) is an open-label, two-arm phase Ib clinical trial. Fourteen patients with advanced and/or metastatic melanoma (stage IIIc/IV) were enrolled. Patients were treated with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) combined to infliximab (5 mg/kg, N = 6) or certolizumab (400/200 mg, N = 8). The primary endpoint was safety and the secondary endpoint was antitumor activity. Adverse events (AEs) were graded according to the NCI Common Terminology Criteria for Adverse Events and response was assessed following RECIST 1.1., Results: Only one dose-limiting toxicity was observed in the infliximab cohort. The two different combinations were found to be safe. We observed lower treatment-related AEs with infliximab as compared with certolizumab. In the certolizumab cohort, one patient was not evaluable for response. In this cohort, four of eight patients exhibited hepatobiliary disorders and seven of seven evaluable patients achieved objective response including four complete responses (CRs) and three partial responses (PRs). In the infliximab cohort, we observed one CR, two PRs, and three progressive diseases. Signs of activation and maturation of systemic T-cell responses were seen in patients from both cohorts., Conclusions: Our results show that both combinations are safe in human and provide clinical and biological activities. The high response rate in the certolizumab-treated patient cohort deserves further investigations., (©2020 American Association for Cancer Research.)

Metabolic reprogramming contributes to the pathogenesis and heterogeneity of melanoma. It is driven both by oncogenic events and the constraints imposed by a nutrient- and oxygen-scarce microenvironment. Among the most prominent metabolic reprogramming features is an increased rate of lipid synthesis. Lipids serve as a source of energy and form the structural foundation of all membranes, but have also emerged as mediators that not only impact classical oncogenic signaling pathways, but also contribute to melanoma progression. Various alterations in fatty acid metabolism have been reported and can contribute to melanoma cell aggressiveness. Elevated expression of the key lipogenic fatty acid synthase is associated with tumor cell invasion and poor prognosis. Fatty acid uptake from the surrounding microenvironment, fatty acid β-oxidation and storage also appear to play an essential role in tumor cell migration. The aim of this review is ( i ) to focus on the major alterations affecting lipid storage organelles and lipid metabolism. A particular attention has been paid to glycerophospholipids, sphingolipids, sterols and eicosanoids, ( ii ) to discuss how these metabolic dysregulations contribute to the phenotype plasticity of melanoma cells and/or melanoma aggressiveness, and ( iii ) to highlight therapeutic approaches targeting lipid metabolism that could be applicable for melanoma treatment.

Cutaneous melanoma is a deadly skin cancer whose aggressiveness is directly linked to its metastatic potency. Despite remarkable breakthroughs in term of treatments with the emergence of targeted therapy and immunotherapy, the prognosis for metastatic patients remains uncertain mainly because of resistances. Better understanding the mechanisms responsible for melanoma progression is therefore essential to uncover new therapeutic targets. Interestingly, the sphingolipid metabolism is dysregulated in melanoma and is associated with melanoma progression and resistance to treatment. This review summarises the impact of the sphingolipid metabolism on melanoma from the initiation to metastatic dissemination with emphasis on melanoma plasticity, immune responses and resistance to treatments.

Immune checkpoint blockers (ICB) have revolutionized cancer therapy. However, complete response is observed in a minority of patients and most patients develop immune-related adverse events (irAEs). These include colitis, which can be treated with anti-tumor necrosis factor (TNF) antibodies such as Infliximab. In a recent issue of the Journal for ImmunoTherapy of Cancer, Badran et al. reported that co-administering Infliximab together with ICB to five cancer patients prevents colitis recurrence, with four of them exhibiting overall disease stability. The basis for this treatment strategy stemmed from our pre-clinical demonstration that TNF contributes to resistance to anti-PD-1 therapy. In agreement with this concept, we have shown that TNF blockers improve the anti-tumor therapeutic activity of ICB in mice and based on these findings we are currently evaluating the combination in melanoma patients enrolled in the TICIMEL clinical trial. Herein, (i) we discuss the scientific rationale for combining anti-TNF and ICB in cancer patients, (ii) comment on the paper published by Badran et al. and (iii) provide the TICIMEL clinical trial design.

New monohalogenated maleimide derivatives (with bromine, chlorine or iodine) were synthesized to test the effect of halogen atoms in inhibiting the formation of Pseudomonas aeruginosa biofilm. The evaluation of their biological activities clearly defines a structure-activity relationship. In this study, the bactericidal action of the three compounds was observed at the concentration range 0.3-5.0 mM on Luria-Bertani agar plates. The halogen atom of these molecules was critical in modulating the antibacterial activity, with a slightly higher effectiveness for chlorine. Confocal laser scanning microscopy was used to examine P. aeruginosa biofilms cultivated in flow cells. At concentration as low as 40 microM, the bromine and iodine compounds displayed a total inhibition towards the formation of bacterial biofilm. At this concentration, the bacterial attachment to glass surfaces was strongly affected by the presence of bromine and iodine whereas the chlorine derivative behaved as a bactericidal compound. A bioluminescent reporter strain was then used to detect the effect of the chemically synthesized maleimides on quorum sensing (QS) in P. aeruginosa. At the concentration range 10-100 microM, bioluminescence assays reveal that halogenated maleimides were able to interfere with the QS of the bacterium. Although the relationship between the weak inhibition of cell-to-cell communication (15-55% of the signal) and the high inhibition of biofilm formation has not been elucidated clearly, the results demonstrate that bromo- and iodo-N-substituted maleimides bromine and iodine may be used as new potent inhibitors that control bacterial biofilms.

A protocol using reversed-phase liquid chromatography coupled with positive-ion electrospray ionization and ion trap mass spectrometry is described for the identification and quantification of N-acylhomoserine lactones (HSLs) in crude cell-free supernatants of bacterial cultures. The HSLs are produced by gram-negative bacteria and act as intercellular signals inducing density-dependent gene expression. Compared with the multi-step procedures previously reported, which included chemical extraction, purification and the use of Escherichia coli HSL biosensors, this on-line LC-MS-MS method is fast and detects 11 HSLs. Its speed and robustness allow the analysis of a large number of samples without loss of performance (no signal variation for a control sample after 90 chromatographic injections). The selectivity is based on the MS-MS fragment ions of the molecular [M+H]- ions and on their relative intensities. For quantification, the m/z 102 ion, specific for the lactone ring and detected with a good signal-to-noise ratio, allows low detection limits even in complex matrix samples (0.28 up to 9.3 pmol). Moreover, this method allows the quantification of 11 HSLs whatever their chemical structure, substituted or not. The protocol was applied to Vibrio vulnificus, a marine bacterium. Six HSLs were detected and quantified with relative standard deviations for repeatability of < 10%.