Boundary Element and Finite Element Coupling for Aeroacoustics Simulations

We consider the scattering of acoustic perturbations in a presence of a flow. We suppose that the space can be split into a zone where the flow is uniform and a zone where the flow is potential. In the first zone, we apply a Prandtl-Glauert transformation to recover the Helmholtz equation. The well-known setting of boundary element method for the Helmholtz equation is available. In the second zone, the flow quantities are space dependent, we have to consider a local resolution, namely the finite element method. Herein, we carry out the coupling of these two methods and present various applications and validation test cases. The source term is given through the decomposition of an incident acoustic field on a section of the computational domain's boundary.Comment: 25 page

Plasma ceramide, a real-time predictive marker of pulmonary and hepatic metastases response to stereotactic body radiation therapy combined with irinotecan

AbstractBackground and purposesEarly biomarkers of tumour response are needed to discriminate between responders and non-responders to radiotherapy. We evaluated the ability of ceramide, a bioactive sphingolipid, to predict tumour sensitivity in patients treated by hypofractionated stereotactic body radiation therapy (SBRT) combined with irinotecan chemotherapy.Materials and methodsPlasma levels of total ceramide and of its subspecies were measured before and during treatment in 35 patients with liver and lung oligometastases of colorectal cancer included in a phase II trial. Cer levels were quantified by LC–ESI-MS/MS and compared to tumour volume response evaluated one year later by CT-scan.ResultsPretreatment plasma ceramide levels were not indicative of tumour response. Nevertheless, the levels of total ceramide and of its 4 main subspecies were significantly higher at days 3 and 10 of treatment in objective responders than in non-responders. According to Kaplan–Meier curves, almost complete tumour control was achieved at 1year in patients with increased total ceramide levels whereas 50% of patients with decreased levels experienced an increase in tumour volume.ConclusionsTotal plasma ceramide is a promising biomarker of tumour response to SBRT combined with irinotecan that should enable to segregate patients with high risk of tumour escape

Identification of Gender- and Subtype-Specific Gene Expression Associated with Patient Survival in Low-Grade and Anaplastic Glioma in Connection with Steroid Signaling

Low-grade gliomas are rare primary brain tumors, which fatally evolve to anaplastic gliomas. The current treatment combines surgery, chemotherapy, and radiotherapy. If gender differences in the natural history of the disease were widely described, their underlying mechanisms remain to be determined for the identification of reliable markers of disease progression. We mined the transcriptomic and clinical data from the TCGA-LGG and CGGA databases to identify male-over-female differentially expressed genes and selected those associated with patient survival using univariate analysis, depending on molecular characteristics (IDH wild-type/mutated; 1p/19q codeleted/not) and grade. Then, the link between the expression levels (low or high) of the steroid biosynthesis enzyme or receptors of interest and survival was studied using the log-rank test. Finally, a functional analysis of gender-specific correlated genes was performed. HOX-related genes appeared to be differentially expressed between males and females in both grades, suggesting that a glioma could originate in perturbation of developmental signals. Moreover, aromatase, androgen, and estrogen receptor expressions were associated with patient survival and were mainly related to angiogenesis or immune response. Therefore, consideration of the tight control of steroid hormone production and signaling seems crucial for the understanding of glioma pathogenesis and emergence of future targeted therapies

Analysis of Signal-Averaged Electrocardiogram Performance for Body Surface Recordings

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Ultrasound-Guided Subclavian Vein Cannulation in Low Birth Weight Neonates

OBJECTIVES: Central venous access in critically ill, small infants remains technically challenging even in experienced hands. Several vascular accesses exist, but the subclavian vein is often preferred for central venous catheter insertion in infants where abdominal malformation and/or closure of the vein preclude the use of umbilical venous catheters, as catheterization of the subclavian vein is easier in very short necks than the internal jugular vein for age-related anatomical reasons. The subclavian vein approach is yet relatively undescribed in low birth weight infants (i.e., \textless 2,500 g), and this study aims to explore the feasibility of this technique in very small infants. DESIGN: Retrospective data collection of prospectively registered data on central venous catheter insertion in infants. SETTING: Neonatal ICU and PICU at a university hospital. PATIENTS: One hundred and five newborn children hospitalized in at the ICU. INTERVENTIONS: An ultrasound-guided supraclavicular approach was applied on all infants who had an subclavian vein catheterization during a 30-month period from January 2013 to July 2015. MEASUREMENTS AND MAIN RESULTS: One hundred seven supraclavicular subclavian vein catheters were placed in 105 children weighing less than 5,000 g. Among those, 40 patients weighed less than 2,500 g and 10 patients weighed less than 1,500 g. Successful central venous catheter insertion, defined as the correct placement of a functional double-lumen catheter (3F or 4F), was obtained in 97.3%. All three registered failed attempts were due to hematomas from venous bleeding and occurred in infants weighing greater than 2,500 g. No case of accidental arterial puncture or pleural puncture was registered. CONCLUSIONS: This large series of subclavian vein catheterizations in small infants demonstrates the feasibility of subclavian vein catheterizations even in very small neonates weighing less than 1,500 g

GPER agonist G-1 disrupts tubulin dynamics and potentiates temozolomide to impair glioblastoma cell proliferation

International audienceGlioblastoma (GBM) is the most common brain tumor in adults, which is very aggressive, with a very poor prognosis that affects men twice as much as women, suggesting that female hormones (estrogen) play a protective role. With an in silico approach, we highlighted that the expression of the membrane G-protein-coupled estrogen receptor (GPER) had an impact on GBM female patient survival. In this context, we explored for the first time the role of the GPER agonist G-1 on GBM cell proliferation. Our results suggested that G-1 exposure had a cytostatic effect, leading to reversible G2/M arrest, due to tubulin polymerization blockade during mitosis. However, the observed effect was independent of GPER. Interestingly, G-1 potentiated the efficacy of temozolomide, the current standard chemotherapy treatment, since the combination of both treatments led to prolonged mitotic arrest, even in a temozolomide less-sensitive cell line. In conclusion, our results suggested that G-1, in combination with standard chemotherapy, might be a promising way to limit the progression and aggressiveness of GBM

Anti-Gb3 monoclonal antibody inhibits angiogenesis and tumor development.

Inhibiting the growth of tumor vasculature represents one of the relevant strategies against tumor progression. Between all the different pro-angiogenic molecular targets, plasma membrane glycosphingolipids have been under-investigated. In this present study, we explore the anti-angiogenic therapeutic advantage of a tumor immunotherapy targeting the globotriaosylceramide Gb3. In this purpose, a monoclonal antibody against Gb3, named 3E2 was developed and characterized. We first demonstrate that Gb3 is over-expressed in proliferative endothelial cells relative to quiescent cells. Then, we demonstrate that 3E2 inhibits endothelial cell proliferation in vitro by slowing endothelial cell proliferation and by increasing mitosis duration. Antibody 3E2 is further effective in inhibiting ex vivo angiogenesis in aorta ring assays. Moreover, 3E2 treatment inhibits NXS2 neuroblastoma development and liver metastases spreading in A/J mice. Immunohistology examination of the NXS2 metastases shows that only endothelial cells, but not cancer cells express Gb3. Finally, 3E2 treatment diminishes tumor vessels density, proving a specific therapeutic action of our monoclonal antibody to tumor vasculature. Our study demonstrates that Gb3 is a viable alternative target for immunotherapy and angiogenesis inhibition

Sphingolipids distribution at mitochondria-associated membranes (MAM) upon induction of apoptosis.

International audienceThe levels and composition of sphingolipids and related metabolites are altered in aging and common disorders such as diabetes and cancers, as well as in neurodegenerative, cardiovascular, and respiratory diseases. Changes in sphingolipids have been implicated as being an essential step in mitochondria-driven cell death. However, little is known about the precise sphingolipid composition and modulation in mitochondria or related organelles. Here, we used LC-MS/MS to analyze the presence of key components of the ceramide metabolic pathway in vivo and in vitro in purified endoplasmic reticulum (ER), mitochondria-associated membranes (MAM), and mitochondria. Specifically, we analyzed the sphingolipids in the three pathways that generate ceramide: sphinganine in the de novo ceramide pathway, sphingomyelin in the breakdown pathway, and sphingosine in the salvage pathway. We observed sphingolipid profiles in mouse liver, mouse brain, and a human glioma cell line (U251). We analyzed the quantitative and qualitative changes of these sphingolipids during staurosporine (STS)-induced apoptosis in U251 cells. Ceramide, especially C16-ceramide, levels increased during early apoptosis possibly through a conversion from mitochondrial sphinganine and sphingomyelin, but sphingosine and lactosyl- and glucosyl-ceramide levels were unaffected. We also found that ceramide generation is enhanced in mitochondria when sphingomyelin levels are decreased in the MAM. This decrease was associated with an increase in acid sphingomyelinase (ASM) activity in MAM. We conclude that meaningful sphingolipid modifications occur in MAM, the mitochondria, and ER during the early phases of apoptosis

Plasma membrane reorganization links acid sphingomyelinase/ceramide to p38 MAPK pathways in endothelial cells apoptosis

International audienceThe p38 MAPK signaling pathway is essential in the cellular response to stress stimuli, in particular in the endothelial cells that are major target of external stress. The importance of the bioactive sphingolipid ceramide generated by acid sphingomyelinase is also firmly established in stress-induced endothelial apoptotic cell death. Despite a suggested link between the p38 MAPK and ceramide pathways, the exact molecular events of this connection remain elusive. In the present study, by using two different activators of p38 MAPK, namely anisomycin and ionizing radiation, we depicted how ceramide generated by acid sphingomyelinase was involved in p38 MAPK-dependent apoptosis of endothelial cells. We first proved that both anisomycin and ionizing radiation conducted to apoptosis through activation of p38 MAPK in human microvascular endothelial cells HMEC-1. We then found that both treatments induced activation of acid sphin-gomyelinase and the generation of ceramide. This step was required for p38 MAPK activation and apoptosis. We finally showed that irradiation, as well as treatment with exogenous C 16-ceramide or bacterial sphingomyelinase, induced in en-dothelial cells a deep reorganization of the plasma membrane with formation of large lipid platforms at the cell surface, leading to p38 MAPK activation and apoptosis in endothelial cells. Altogether, our results proved that the plasma membrane reorganization leading to ceramide production is essential for stress-induced activation of p38 MAPK and apoptosis in endothelial cells and established the link between the acid sphingomyelinase/ceramide and p38 MAPK pathways