B-RAF Mutant Alleles Associated with Langerhans Cell Histiocytosis, a Granulomatous Pediatric Disease

Langerhans cell histiocytosis (LCH) features inflammatory granuloma characterised by the presence of CD1a+ dendritic cells or 'LCH cells'. Badalian-Very et al. recently reported the presence of a canonical (V600E)B-RAF mutation in 57% of paraffin-embedded biopsies from LCH granuloma. Here we confirm their findings and report the identification of two novel B-RAF mutations detected in LCH patients.Mutations of B-RAF were observed in granuloma samples from 11 out of 16 patients using 'next generation' pyrosequencing. In 9 cases the mutation identified was (V600E)B-RAF. In 2 cases novel polymorphisms were identified. A somatic (600DLAT)B-RAF insertion mimicked the structural and functional consequences of the (V600E)B-RAF mutant. It destabilized the inactive conformation of the B-RAF kinase and resulted in increased ERK activation in 293 T cells. The (600DLAT)B-RAF and (V600E)B-RAF mutations were found enriched in DNA and mRNA from the CD1a+ fraction of granuloma. They were absent from the blood and monocytes of 58 LCH patients, with a lower threshold of sequencing sensitivity of 1%-2% relative mutation abundance. A novel germ line (T599A)B-RAF mutant allele was detected in one patient, at a relative mutation abundance close to 50% in the LCH granuloma, blood monocytes and lymphocytes. However, (T599A)B-RAF did not destabilize the inactive conformation of the B-RAF kinase, and did not induce increased ERK phosphorylation or C-RAF transactivation.Our data confirmed presence of the (V600E)B-RAF mutation in LCH granuloma of some patients, and identify two novel B-RAF mutations. They indicate that (V600E)B-RAF and (600DLAT)B-RAF mutations are somatic mutants enriched in LCH CD1a(+) cells and absent from the patient blood. Further studies are needed to assess the functional consequences of the germ-line (T599A)B-RAF allele

On The Impact of a Series of Severe Storms on a Double-Barred Sandy Coast: Dune Erosion and Megacups Embayments

International audienceThe winter of 2013/2014 was outstanding in terms of the available energy to move sediment and caused large-scale unprecedented erosion of the Gironde coast (France), comprising the onset of megacusp embayments cutting the dune with a typical alongshore and cross-shore lengthscale of O (100 m) and O(10 m), and a dune erosion scarp height often exceeding 10 m. Megacusps are found to be coupled to the outer crescentic sandbar and triggered by the outstandingly high-energy, long-period and normally-incident storm wave event Hercules on January 6-7. Our observations indicate that both the antecedent outer sandbar morphology and storm wave characteristics, including period and angle of incidence, govern patterns of beach and dune erosion along open multiple-barred sandy coasts during severe storms

Impact of the winter 2013–2014 series of severe Western Europe storms on a double-barred sandy coast: Beach and dune erosion and megacusp embayments

International audienceThe winter of 2013/2014 was characterized by a striking pattern of temporal and spatial extreme storm wave clustering in Western Europe. The 110-km long Gironde coast, SW France, was exposed to the most energetic wave conditions over the last 18 years. The period was outstanding in terms of the available energy to move sediment and cause large-scale erosion with the 2-month average significant wave height (Hs) exceeding 3.6 m, just below the 0.95 quantile, and 4 distinct 10-year return period storms with Hs > 9 m. These storm waves caused unprecedented beach and dune erosion along the Gironde coast, including severely damaged sea defences at the coastal towns. At the end of the winter, dune erosion scarp height was highly variable alongshore and often exceeded 10 m. Megacusp embayments were observed along the Gironde coast with an average alongshore spacing of 1000 m in the south progressively decreasing to 500 m in the north, with an average cross-shore amplitude of 20 m. While beach megacusps were previously observed to systematically couple to the inner bar along the Gironde coast during low- to moderate-energy wave conditions, severe storm-driven megacusp embayments cutting the dune were found to be enforced and coupled to the outer crescentic bar. A detailed inspection of the 1500 m-long bimonthly topographic surveys of Truc Vert beach shows that in early January 2014 the outstanding shore-normal incident storm swell ‘Hercules’, with Hs and peak wave period Tp peaking at 9.6 m and 22 s, respectively, triggered the formation of a localized megacusp embayment with the erosion scarp height exceeding 6 m in its centre where the dune retreat reached 30 m. The subsequent storms progressively smoothed the megacusp by the end of the winter, mostly through severe erosion of the megacusp horns. Because of the very long period (16 s < Tp < 23 s) storm waves with persistent shore-normal incidence, the well-developed outer crescentic bar observed prior to the winter did not straighten. Instead, the outer-bar three-dimensionality developed further, particularly during ‘Hercules’. Our observations indicate that both the antecedent outer sandbar morphology and storm wave characteristics, including period and angle of incidence, govern patterns of beach and dune erosion along open multiple-barred sandy coasts during severe storms

Relative Contribution of Wave Setup to the Storm Surge: Observations and Modeling Based Analysis in Open and Protected Environments (Truc Vert beach and Tubuai island)

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Arabidopsis PECTIN METHYLESTERASE17 is co-expressed with and processed by SBT3.5, a subtilisin-like serine protease

International audienceBackground and Aims In Arabidopsis thaliana, the degree of methylesterification (DM) of homogalacturonans (HGs), the main pectic constituent of the cell wall, can be modified by pectin methylesterases (PMEs). In all organisms, two types of protein structure have been reported for PMEs: group 1 and group 2. In group 2 PMEs, the active part (PME domain, Pfam01095) is preceded by an N-terminal extension (PRO part), which shows similarities to PME inhibitors (PMEI domain, Pfam04043). This PRO part mediates retention of unprocessed group 2 PMEs in the Golgi apparatus, thus regulating PME activity through a post-translational mechanism. This study investigated the roles of a subtilisin-type serine protease (SBT) in the processing of a PME isoform. Methods Using a combination of functional genomics, biochemistry and proteomic approaches, the role of a specific SBT in the processing of a group 2 PME was assessed together with its consequences for plant development. Key Results A group 2 PME, AtPME17 (At2g45220), was identified, which was highly co-expressed, both spatially and temporally, with AtSBT3.5 (At1g32940), a subtilisin-type serine protease (subtilase, SBT), during root development. PME activity was modified in roots of knockout mutants for both proteins with consequent effects on root growth. This suggested a role for SBT3.5 in the processing of PME17 in planta. Using transient expression in Nicotiana benthamiana, it was indeed shown that SBT3.5 can process PME17 at a specific single processing motif, releasing a mature isoform in the apoplasm. Conclusions By revealing the potential role of SBT3.5 in the processing of PME17, this study brings new evidence of the complexity of the regulation of PMEs in plants, and highlights the need for identifying specific PME-SBT pairs

Quel impact du nouveau règlement européen sur la protection des données sur la recherche clinique et recommandations

International audienceLa recherche clinique, menée sur des sujets humains ou à partir de leurs données, se trouve confrontée à des exigences contradictoires, avec, d’une part, le principe de science ouverte (transparence et partage des données), les possibilités offertes par les « big data » et la réutilisation des données issues de la recherche ou du soin et, d’autre part, l’encadrement réglementaire et législatif qui évolue, avec notamment le règlement général sur la protection des données ou RGPD. Une table ronde était organisée à Giens en octobre 2018, afin d’identifier les zones de tension, les besoins de clarification et de fluidification, et de faire des recommandations visant à promouvoir la recherche clinique tout en assurant un haut niveau de protection des patients. Après une mise au point effectuée en commun sur ces évolutions, les participants à la table ronde ont pu proposer des recommandations, dont les principales sont (1) de clarifier : ce qui est considéré comme données anonymisées et ce que représente « l’intérêt public » au sens du RGPD ; (2) de poursuivre le développement des méthodologies de référence par la CNIL ; (3) de promouvoir l’utilisation secondaire des données, en facilitant une information et un consentement élargi des patients, en clarifiant les circonstances d’application de leurs droits de retrait, d’opposition, de façon à limiter le risque de biais ; (4) faciliter l’accès aux entrepôts de données par la mise à disposition de supports technologiques et méthodologiques. Enfin, développer les échanges au niveau européen entre autorités sur les sujets de recherche, promouvoir la participation des autorités françaises à l’élaboration des codes de conduite, et la mise en place d’une procédure d’harmonisation volontaire pour coordonner les avis des autorités de protection des données, tout en s’assurant que les principaux documents soient disponibles en langue anglaise

Pregnancy After Breast Cancer in Patients With Germline Mutations.

PURPOSE: Young women with germline BRCA mutations have unique reproductive Challenges. Pregnancy after breast cancer does not increase the risk of recurrence; however, very limited data are available in patients with BRCA mutations. This study investigated the impact of pregnancy on breast cancer outcomes in patients with germline BRCA mutations. PATIENTS AND METHODS: This is an international, multicenter, hospital-based, retrospective cohort study. Eligible patients were diagnosed between January 2000 and December 2012 with invasive early breast cancer at age ≤ 40 years and harbored deleterious germline BRCA mutations. Primary end points were pregnancy rate, and disease-free survival (DFS) between patients with and without a pregnancy after breast cancer. Pregnancy outcomes and overall survival (OS) were secondary end points. Survival analyses were adjusted for guarantee-time bias controlling for known prognostic factors. RESULTS: Of 1,252 patients with germline BRCA mutations (BRCA1, 811 patients; BRCA2, 430 patients; BRCA1/2, 11 patients) included, 195 had at least 1 pregnancy after breast cancer (pregnancy rate at 10 years, 19%; 95% CI, 17% to 22%). Induced abortions and miscarriages occurred in 16 (8.2%) and 20 (10.3%) patients, respectively. Among the 150 patients who gave birth (76.9%; 170 babies), pregnancy complications and congenital anomalies occurred in 13 (11.6%) and 2 (1.8%) cases, respectively. Median follow-up from breast cancer diagnosis was 8.3 years. No differences in DFS (adjusted hazard ratio [HR], 0.87; 95% CI, 0.61 to 1.23; P = .41) or OS (adjusted HR, 0.88; 95% CI, 0.50 to 1.56; P = .66) were observed between the pregnancy and nonpregnancy cohorts. CONCLUSION: Pregnancy after breast cancer in patients with germline BRCA mutations is safe without apparent worsening of maternal prognosis and is associated with favorable fetal outcomes. These results provide reassurance to patients with BRCA-mutated breast cancer interested in future fertility. TRIAL REGISTRATION: ClinicalTrials.gov NCT03673306