Obésité et grossesse (étude de l'influence d'un marqueur de l'obésité sur les mécanismes cellulaires et tissulaires de l'accouchement dans un modèle d'explants myométriaux humains)

L obésité maternelle, dont la prévalence ne cesse d augmenter, est associée à de nombreux troubles de l accouchement, tels que des dépassements de terme à l origine d une augmentation du taux de césariennes. Ces troubles pourraient, en partie, s expliquer par une concentration plasmatique de leptine plus élevée chez les femmes enceintes obèses ainsi que par les effets inhibiteurs, démontrés in vitro, de cette adipokine sur la contractilité myométriale. Au moment de l accouchement, la transition phénotypique du myomètre d un état de quiescence utérine à un état contractile est une étape clé indispensable à la mise en route du travail. Elle est associée à une activation de l apoptose des cellules myométriales ainsi qu à un remodelage de la matrice extracellulaire utérine. Le but de notre travail était d étudier la capacité de la leptine à moduler l apoptose et le remodelage myométriaux induits par le lipopolysaccharide (LPS).Les échantillons de myomètre ont été prélevés lors de césariennes réalisées avant la mise en route du travail, à la maternité du CHU de Dijon. Les effets de la leptine ont été évalués après incubation des explants myométriaux pendant 48 heures avec du LPS (10 g/ml) avec ou sans leptine (de 10-10 à 10-8 M).Nos résultats ont démontré la capacité de la leptine à inhiber, de façon concentration-dépendante, l apoptose induite par le LPS en diminuant l expression des protéines pro-apoptotiques (caspase-3 clivée, BAX) et en augmentant celle du médiateur anti-apoptotique BCL2. Cet effet anti-apoptotique de la leptine dans le myomètre gestant était associé à l activation de la voie de signalisation ERK1/2. De plus, nos résultats ont montré que la leptine était également capable de s opposer, de façon concentration-dépendante, à la dégradation du collagène de la matrice extracellulaire myométriale induite par le LPS. Cet effet était associé à l inhibition de l activation et de la surexpression des métalloprotéinases MMP2 et MMP9 induites par le LPS.Ce travail a permis d approfondir les connaissances sur le rôle de la leptine dans la régulation de l'activité du myomètre. Nos résultats suggèrent que les troubles de l accouchement observés chez les femmes obèses résulteraient de l inhibition de l apoptose et du remodelage myométriaux par la leptine, en plus de l inhibition de la contractilité utérine déjà décrite.Maternal obesity is associated with a wide spectrum of delivery disorders, such as delayed or post-term delivery, that might be explained partly by the increase in plasma leptin levels in obese women, as leptin inhibits in vitro myometrial contractility. Delivery involves uterine apoptosis and remodelling of the extracellular matrix, via the activation of matrix metalloproteinases (MMP). This study was aimed to assess the role of leptin on human myometrium, by studying the interaction of leptin with lipopolysaccharide (LPS)-induced apoptosis and degradation of myometrial collagen.Myometrial biopsies were obtained from women undergoing caesarean delivery before labour onset. The effects of leptin on myometrial apoptosis and remodelling were assessed by incubating the strips for 48h with LPS (10 g/ml) alone or with leptin (from 10-10 to 10-8 M).Leptin prevented LPS-induced apoptosis, in a concentration-dependent manner, by down-regulating cleaved caspase-3, BAX and up-regulating BCL2 expression. This effect was specifically mediated through leptin receptors stimulation followed by ERK1/2 signalling pathway activation. Leptin prevented, in a concentration-dependent manner, an LPS-induced decrease in myometrial collagen content, and this effect was associated with a decrease in MMP2 and MMP9 activity and overexpression. These effects of leptin were abolished by pre-treatment with a selective leptin receptor antagonist. These results suggest new potential pathways involved in delivery disorders of obese women and propose a role for leptin-induced inhibition of myometrial apoptosis and extracellular matrix remodelling in the development of such disorders.DIJON-BU Doc.électronique (212319901) / SudocSudocFranceF

Pharmacokinetics, pharmacodynamics and clinical efficacy of omalizumab for the treatment of asthma.

IF 2.598International audienceOmalizumab is a subcutaneously administrated monoclonal anti-IgE antibody indicated in adults, adolescents and children 6 years of age and older with moderate to severe allergic asthma uncontrolled by conventional pharmacological treatments and sensitization to at least one perennial allergen. Area covered: This drug evaluation summarizes published data on pharmacokinetic and pharmacodynamic properties of omalizumab, on clinical efficacy and safety, including real-world evidence, and provides a medico-economic evaluation of the drug. Expert opinion: Omalizumab represents an efficient therapeutic option for the management of patients with uncontrolled moderate/severe allergic asthma. It provides a significant reduction in the asthma exacerbation rate with a steroid-sparing effect, an improvement in quality of life in adults and adolescents, despite a lack of evidence about its efficacy specifically in severe allergic asthma. Clinical trials have demonstrated its efficacy in the pediatric population but further real-life evidence is expected to better characterize long-term effects in this population. There is still some debate about the optimal treatment duration but, to date, it is recommended not to stop the treatment as cessation has resulted in symptom recurrence. Omalizumab is an expensive treatment, but a key therapeutic option when used for uncontrolled severe allergic asthma

[Level of evidence for therapeutic drug monitoring of everolimus].

International audienceEverolimus has proven efficacy for prevention of rejection in adult de novo renal and cardiac transplant recipient in combination with ciclosporine and corticosteroids. Therapeutic drug monitoring (TDM) with target trough concentration (C0) value from 3 to 8 µg/L has been proposed. Through a systematic review of the literature, this work explored a level of recommendation for this TDM. Everolimus exhibits both wide interindividual pharmacokinetic variability and poor relationship between dose and exposure. A good relationship has been reported between C0 values and global exposure to the drug (i.e. AUC). Although C0 > 3 µg/L has been associated with a decreased incidence of rejection, the upper limit of 8 µg/L has never been formally validated. No clinical trial testing other exposure indices or comparing efficacy and/or toxicity of everolimus therapy with and without TDM has been published so far. Consequently the level of recommendation for everolimus monitoring is "recommended"

Extracellular Heat Shock Proteins as Therapeutic Targets and Biomarkers in Fibrosing Interstitial Lung Diseases

Interstitial lung diseases (ILDs) include a large number of diseases and causes with variable outcomes often associated with progressive fibrosis. Although each of the individual fibrosing ILDs are rare, collectively, they affect a considerable number of patients, representing a significant burden of disease. Idiopathic pulmonary fibrosis (IPF) is the typical chronic fibrosing ILD associated with progressive decline in lung. Other fibrosing ILDs are often associated with connective tissues diseases, including rheumatoid arthritis-ILD (RA-ILD) and systemic sclerosis-associated ILD (SSc-ILD), or environmental/drug exposure. Given the vast number of progressive fibrosing ILDs and the disparities in clinical patterns and disease features, the course of these diseases is heterogeneous and cannot accurately be predicted for an individual patient. As a consequence, the discovery of novel biomarkers for these types of diseases is a major clinical challenge. Heat shock proteins (HSPs) are molecular chaperons that have been extensively described to be involved in fibrogenesis. Their extracellular forms (eHSPs) have been recently and successfully used as therapeutic targets or circulating biomarkers in cancer. The current review will describe the role of eHSPs in fibrosing ILDs, highlighting the importance of these particular stress proteins to develop new therapeutic strategies and discover potential biomarkers in these diseases

How can we best monitor 5-FU administration to maximize benefit to risk ratio?

International audience5-Fluorouracil (5-FU) is currently used as a chemotherapy in several cancers such as head-and-neck (H&N) and colorectal cancers. 5-FU dosing is traditionally based on body surface area (BSA), but this strategy is usually associated with severe toxicities. 5-FU is mainly catabolized by dihydropyrimidine dehydrogenase (DPD), and 5-FU dosage adaptation according to DPD status at the first cycle of treatment is now recommended. To further optimize 5-FU-based chemotherapy, a body of evidences justifies therapeutic drug monitoring (TDM). Areas covered: 5-FU pharmacokinetics, relationships between pharmacokinetics and efficacy or toxicity of 5-FU, proofs of interest of 5-FU TDM and its practical considerations are discussed. Expert opinion: BSA-adjusted 5-FU administration is associated with a large inter-individual variability, and according to this strategy, many patients experience under- or overexposure. Moreover, relationships between 5-FU area under the curve (AUC) and its toxicity or efficacy have been demonstrated, at least in patients with colorectal or H&N cancers. 5-FU therapeutic index has been validated and algorithms of 5-FU dosage adaptation according to its AUC are now available. Advances in pre-analytical and analytical steps of 5-FU TDM make its use feasible in clinical practice. Thus, there are consistent evidences to recommend 5-FU TDM in patients with advanced colorectal or H&N cancers

Postnatal overfeeding in rats leads to moderate overweight and to cardiometabolic and oxidative alterations in adulthood

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LSC Abstract – Pleural inflammation is essential in bleomycin-induced lung toxicity

IF 10.569International audienceIntroduction: In patients, the therapeutic use of bleomycin (BLM), a potent anticancerous drug, is strongly restrained because of its lung toxicity with pulmonary fibrosis (PF) being the most devastating form. Toxic and Idiopathic PF start classically in the subpleural area. It is know that 1) Pleural mesothelial cells (PMCs) acquire a TGF-β1-induced myofibroblast phenotype and 2) inflammation plays a significant role in fibrogenesis. The role of mesothelial cells in PF and in BLM lung toxicity has still to be investigated.Methods: C57Bl/6 mice were intravenously (IV) injected with BLM or NaCl. In vitro, human pleural mesothelial cells (Met5A) were treated with BLM.Results: Repeated IV BLM induces a peculiar lung fibrotic response with 1) an histological peripheral distribution, 2) a collagen accumulation in pleural and subpleural area, 3) an overexpression in PMCs of MMP-2, -9, HSP27, all involved in myofibroblast tranformation and 4) a migration of PMCs into the lung. This process was associated with an inflammatory profile with an increase 1) in neutrophils in pleural lavage fluid (PLF) and 2) an enhanced caspase-1 activity (total lung tissue). TGF-β1 was overexpressed in PLF. TGF-β1 and collagen accumulations were hampered after pleural inhibition of IL-1β (Anakinra intrapleural injection). IV administration of BLM triggered cell death in pleural and subpleural area (TUNEL). In vitro, BLM-induced cell death correlated with an increase in caspase-1 activity.Conclusion: IV BLM in rodent induces subpleural PF as observed in toxic and idiopathic PF in human. Our results demonstrate a key role of PMCs and suggest a caspase-1 dependent inflammation in this fibrogenesis process

Pleural inhibition of the caspase-1/IL-1β pathway diminishes profibrotic lung toxicity of bleomycin

IF 3.751International audienceBackground: Idiopathic and toxic pulmonary fibrosis are severe diseases starting classically in the subpleural area of the lung. It has recently been suggested that pleural mesothelial cells acquire a myofibroblast phenotype under fibrotic conditions induced by TGF-beta 1 or bleomycin. The importance and role of inflammation in fibrogenesis are still controversial. In this work, we explored the role of IL-1 beta/caspase-1 signaling in bleomycin lung toxicity and in pleural mesothelial cell transformation.Methods: C57BL/6 mice were intravenously injected with either bleomycin or nigericin or NaCl as control. In vitro, the Met5A cell line was used as a model of human pleural mesothelial cells.Results: Intravenous injections of bleomycin induced lung fibrosis with histologically-proven peripheral distribution, collagen accumulation in the pleural and subpleural area, and overexpression of markers of myofibroblast transformation of pleural cells which migrated into the lung. These events were associated with an inflammatory process with an increase in neutrophil recruitment in pleural lavage fluid and increased caspase-1 activity. TGF-beta 1 was also overexpressed in pleural lavage fluid and was produced by pleural cells following intravenous bleomycin. In this model, local pleural inhibition of IL-1 beta with the IL-1 beta inhibitor anakinra diminished TGF-beta 1 and collagen accumulation. In vitro, caspase-1 inhibition interfered with Met5A cell transformation into the myofibroblast-like phenotype induced by bleomycin or TGF-beta 1. Moreover, nigericin, a caspase-1 activator, triggered transformation of Met5A cells and its intra-pleural delivery induced fibrogenesis in mice.Conclusions: We demonstrated, after intravenous bleomycin injection in mice, the role of the pleura and highlighted the key role of IL-1 beta/caspase-1 axis in this fibrogenesis process

5-FU therapeutic drug monitoring as a valuable option to reduce toxicity in patients with gastrointestinal cancer

IF 5.168International audienceAims:5-FU is used as the main backbone of chemotherapy regimens for patients with colorectal and other gastrointestinal cancers. Despite development of new strategies that allowed enhancing clinical effectiveness and tolerability of 5-FU, 10-30% of patients treated with 5-FU-based regimens experience severe treatment-related toxicity. In our study, we evaluated the 5-FU exposure-toxicity relationship and investigated the efficacy of PK-guided dosing in increasing tolerability of 5-FU-based chemotherapy.Results:50.7% of patients required dose adjustments after cycle 1. Percentage of patients within 5-FU AUC range was 49.3%, 66.9%, 61.0% at cycle 1, 2 and 3 respectively (p = 0.002 cycle 1 vs cycle 2). At all 3 cycles, lower incidences of grade I/II toxicities were observed for patients below or within range compared with those above range (19.4% vs 41.3%, p < 0.001 respectively).Conclusions:Our analysis confirms that the use of BSA-guided dosing results in highly variable 5-FU exposure and strongly suggests that PK-guided dosing can improve tolerability of 5-FU based chemotherapy in patients with gastrointestinal cancers, thus supporting 5-FU therapeutic drug monitoring.Methods:155 patients with gastrointestinal cancers, who were to receive 5-FU-based regimens were included in our study. At cycle 1, the 5-FU dose was calculated using patient's Body Surface Area (BSA) method. A blood sample was drawn on Day 2 to measure 5-FU concentration. At cycle 2, the 5-FU dose was adjusted using a PK-guided dosing strategy targeting a plasma AUC range of 18-28 mg·h/L, based on cycle 1 concentration. Assessments of toxicity was performed at the beginning of every cycle

P087 Inhibition of pleural inflammation hampers with bleomycin-induced lung profibrotic toxicity.

IF 2.824International audienceThe clinical use of bleomycin is restrained because of its lung toxicity with pulmonary fibrosis being the most devastating form. Toxic and idiopathic pulmonary fibrosis (PF) start classically in the subpleural area. It is known that 1) pleural mesothelial cells (PMCs) acquire a TGF-beta1-induced myofibroblast phenotype and 2) inflammation plays a significant role in fibrogenesis. The role of mesothelial cells in PF and in bleomycin lung toxicity has still to be investigated.C57Bl/6 mice were intravenously injected with bleomycin or NaCl. Repeated intravenous bleomycin induces a peculiar lung fibrotic response with 1) an histological peripheral distribution, 2) a collagen accumulation in pleural and subpleural area, 3) an overexpression of MMP-2, -9, HSP27, all involved in PMCs transformation and 4) a migration of PMCs into the lung...