Direct dating of mid-crustal shear zones with synkinematic allanite:new in situ U-Th-Pb geochronological approaches applied to the Mont Blanc massif

International audienceDating the timing of motion on crustal shear zones is of tremendous importance for understanding the assembly of orogenic terranes. This objective is achieved in this paper by combining petrological and structural observations with novel developments in in situ U-Th-Pb geochronology of allanite. A greenschist facies shear zone within the Mont Blanc Massif is documented. Allanite is synkinematic and belongs to the mylonitic assemblage. LA-ICP-MS U-Th-Pb isotope analyses of allanite reveal high contents and highly radiogenic isotopic compositions of the common-Pb component. The use of measured Pb-isotope compositions of associated minerals (feldspars and chlorite) is critical for accurate common-Pb correction, and provides a powerful mechanism for linking allanite growth to the metamorphic assemblage. A mean 208Pb/232Th age of 29.44 ± 0.95 Ma is accordingly taken for synkinematic allanite crystallisation under greenschist facies conditions. This age reflects the timing of the Mont Blanc underthrusting below the Penninic Front and highlights the potential of directly dating deformation with allanite

New P-T-t data on the metamorphic sole of the Amasia ophiolites and implications for the geodynamical process, NW of the Sevan-Akera suture zone, Lesser Caucasus (Armenia)

International audienceThe ophiolites of the Lesser Caucasus belong to the Tethyan Ophiolitic Belt. In the northwestern part of the Sevan Akera suture zone (Lesser Caucasus, Armenia) ophiolites correspond to a major obduction of oceanic crust over the South Armenian continental block. Near the locality of Amasia (NW Armenia), our mapping evidenced a series of (1) unmetamorphosed gabbroic oceanic crust, resting on (2) serpentinites and a greenschist grade tectonic mélange composed of deformed pillow-basalts, radiolarites and cherts, and (3) a basal slice of garnet amphibolites bearing similar compositional features as the ophiolite. They are sliced by post Eocene thrusts related to the shortening of the suture after the collision of the South Armenian Block (Sosson et al., 2010). Structural observations allow us to consider these metamorphic rocks (garnet amphibolites and quartz-garnet-oligoclase-amphibole-chlorite schistes) to be the sole of the obducted ophiolite. The metamorphic rocks allow the evaluation of pressure-temperature-time conditions endured by the base of the oceanic crust during the obduction of the Armenian ophiolite series. Pressure and temperature estimations were obtained by calculating equilibrium conditions between different mineral phases which coexist in the sample coupled with whole rock geochemistry using the software PERPLEX. The P-T data show a counterclockwise path with (1) a HT-LP peak of P = 6-7 kbar and T > 630_C, followed by MP-MT peak at P = 8-10 kbar and T = 600_C. In order to further constrain the evolution of the amphibolites and build a P-T-t path using 40Ar/39Ar dating on amphiboles and white micas (phengite). The ages obtained on both HT and MT peaks are similar within error (90.8 Ma ± 3.0 (2σ), and 90.8 Ma ± 1.2 (2 σ), respectively), which suggests a very rapid cooling of the metamorphic sole during its stacking in the subduction zone. The counterclockwise path determined confirms the observations made below the Oman ophiolite by Goffé et al. (1988). This path is also in agreement with a scaling process of oceanic crust during the obduction. In this scenario slices of oceanic crust would have been dragged under the obduction front below a relatively hot oceanic crust. Afterwards, these slices would then have been amphibolitized along a HT-MP geothermal gradient. Rapidly, a thickening of the system at c. 91-90 Ma, and underthrusting of amphibolites would have caused the conditions to change to MP-MT. This infers that the South Armenian Block enters the subduction zone at this date. A recent study has shown metamorphic rocks in the same structural setting were affected by a HP metamorphism in the Blue Schist facies (Rolland et al., 2009). The age of this blue schist of Stepanavan, Armenia is slightly older (95-91 Ma) (Galoyan et al., 2009) than the amphibolites of Amasia (91-90 Ma). This assumes the occurrence of an active subduction just before the development of the HT-MP metamorphism of Amasia. References: Galoyan, G., Rolland, Y., Sosson, M., Corsini, M., Billo, S., Verati, C., Melkonyan, R., 2009. Geology, geochemistry and 40Ar/39Ar dating of the Sevan ophiolites (Lesser Caucasus, Armenia): Evidence for Jurassic Back-arc opening and hot spot event between the South Armenian Block and Eurasia. Journal of Asian Earth Science, 34, 135-153. Goffé, B., Michard, A., Kienast, J.R., Le Mer, O., 1988. A case of obduction-related high-pressure, lowtemperature metamorphism in upper crustal nappes, Arabian continental margin, Oman: P-T paths and kinematic interpretation. Tectonophysics, 151, 363-386. Rolland, Y., Billo, S., Corsini, M., Sosson, M., Galoyan, G., 2009. Blueschists of the Amassia-Stepanavan Suture Zone (Armenia): linking Tethys subduction history from E-Turkey toW-Iran. International Journal of Earth Science, 98, 533-550. Sosson, M., Rolland, Y., Müller, C., Danelian, T., Melkonyan, R., Kekelia, S., Adamia, S., Badazadeh, V., Kangarli, T., Avagyan, A., Galoyan, G., Mosar, J., 2010. Subduction, obduction and collision in the Lesser Caucasus (Armenia, Azernaijan, Georgia), new insights. Geological Society, London, Special Publications, 340, 329-352

The Armenian and NW Anatolian ophiolites: new insights for the closure of the Tethys domain and obduction onto the South Armenian Block and Anatolian-Tauride Platform before collision through dynamic modeling

International audienceIn the Lesser Caucasus three main domains are distinguished from SW to NE: (1) the South Armenian Block (SAB), a Gondwanian-derived continental terrane; (2) scattered outcrops of ophiolites coming up against the Sevan-Akera suture zone; and (3) the Eurasian plate. The Armenian ophiolites represent remnants of an oceanic domain which disappeared during Eurasia-Arabia convergence. Previous works using geochemical whole-rock analyses, 40Ar/39Ar and paleontological dating have shown that the ophiolite outcrops throughout this area were emplaced during the Late Cretaceous as one non-metamorphic preserved ophiolitic nappe of back-arc origin that formed during Middle to Late Jurassic. From these works, tectonic reconstructions include two clearly identified subductions, one related to the Neotethys subduction beneath the Eurasian margin and another to intra-oceanic subduction responsible for the opening of the back-arc basin corresponding to the ophiolites of the Lesser Caucasus. The analysis of the two stages of metamorphism of the garnet amphibolites of the ophiolite obduction sole at Amasia (M1: HT-LP peak of P = 6-7 kbar and T > 630°C; M2; MP-MT peak at P = 8-10 kbar and T = 600°C) has allowed us to deduce the onset of subduction of the SAB at 90 Ma for this locality, whichage coincides with other paleontological ages at the obduction front. A preliminary paleomagnetic survey has also brought quantification to the amount of oceanic domain which disappeared by subduction between the SAB and Eurasia before collision. We propose a dynamic finite element model using ADELI to test the incidence of parameters such as the density of the different domains (or the interval between the densities), closing speed (or speeds if sporadic), the importance and interactions of mantle discontinuities with the subducting lithosphere and set a lithospheric model. Our field observations and analyses are used to validate combinations of factors. The aim is to better qualify the predominant factors and quantify the conditions leading to the onset of obduction, the paradox of dense oceanic lithosphere emplaced on top of a continental domain, after subduction and prior to collision. The results of this modeling are also compared to new observations of the assumed eastward extension of this ophiolitic nappe in NW Anatolia. Analyses of the Refahiye ophiolites show similar geochemical signatures as the Armenian ophiolites, due to a similar setting of formation (back-arc). The impact of the obduction of such a vast oceanic domain is not to be taken for granted when considering the following collision stage

Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma

Correction: Volume: 119 Pages: 200-201 DOI: 10.1016/j.ejca.2019.04.012 Published: SEP 2019Background: Nivolumab-ipilimumab demonstrated a survival benefit over sunitinib in first-line setting for metastatic renal cell carcinomas (mRCCs) and is becoming a new standard of care for naive patients with intermediate or poor risk prognosis (International mRCC Database Consortium). The efficacy of subsequent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) after nivolumab-ipilimumab failure remains unclear. Methods: Medical records of mRCC patients treated with nivolumab-ipilimumab, who received subsequent TKI, as part of Checkmate 214 study were reviewed in 13 institutions. Baseline characteristics, outcome data including progression-free survival (PFS), response, overall survival (OS) and toxicities were retrospectively collected. Results: Overall 33 patients received subsequent TKI after nivolumab-ipilimumab failure. Median follow-up from start of subsequent TKI is 22 months (19-NR). Best response was assessed in 30 patients: 12 partial responses (36%), 13 stable diseases (39%) and five progressive diseases (15%). Median PFS from start of TKI was 8 months [5-13]. Median PFS with first-generation (sunitinib/pazopanib) and second-generation TKI (axitinib/cabozantinib) was 8 months [5-16] and 7 months (5-NA), respectively. PFS in second line was significantly longer in patients with a long first-line duration of response to the double immune checkpoint blockade (>= 6 months) with 8 versus 5 months for short responder (= 3. Conclusion: This is the first report of outcomes with TKI, after first-line nivolumab-ipilimumab failure. Median PFS suggests a sustained benefit of TKI and supports trials investigating the optimal sequence. (C) 2018 Published by Elsevier Ltd.Peer reviewe

Human cytomegalovirus infection is associated with increased expression of the lissencephaly gene PAFAH1B1 encoding LIS1 in neural stem cells and congenitally infected brains

peer reviewedCongenital infection of the central nervous system by human cytomegalovirus (HCMV) is a leading cause of permanent sequelae, including mental retardation or neurodevelopmental abnormalities. The most severe complications include smooth brain or polymicrogyria, which are both indicative of abnormal migration of neural cells, although the underlying mechanisms remain to be determined. To gain better insight on the pathogenesis of such sequelae, we assessed the expression levels of a set of neurogenesis-related genes, using HCMV-infected human neural stem cells derived from embryonic stem cells (NSCs). Among the 84 genes tested, we found dramatically increased expression of the gene PAFAH1B1, encoding LIS1 (lissencephaly-1), in HCMV-infected versus uninfected NSCs. Consistent with these ndings, western blotting and immunouorescence analyses conrmed the increased levels of LIS1 in HCMV-infected NSCs at the protein level. We next assessed the migratory abilities of HCMV-infected NSCs and observed that infection strongly impaired the migration of NSCs, without detectable effect on their proliferation. Moreover, we observed increased immunostaining for LIS1 in brains of congenitally infected fetuses, but not in control samples, highlighting the clinical relevance of our ndings. Of note, PAFAH1B1 mutations (resulting in either haploinsufciency or gain of function) are primary causes of hereditary neurodevelopmental diseases. Notably, mutations resulting in PAFAH1B1 haploinsufciency cause classic lissencephaly. Taken together, our ndings suggest that PAFAH1B1 is a critical target of HCMV infection. They also shine a new light on the pathophysiological basis of the neurological outcomes of congenital HCMV infection, by suggesting that defective neural cell migration might contribute to the pathogenesis of the neurodevelopmental sequelae of infectio

Usefulness and pitfalls of MAA SPECT/CT in identifying digestive extrahepatic uptake when planning liver radioembolization

International audiencePURPOSE: Identifying gastroduodenal uptake of (99m)Tc-macroaggregated albumin (MAA), which is associated with an increased risk of ulcer disease, is a crucial part of the therapeutic management of patients undergoing radioembolization for liver tumours. Given this context, the use of MAA single photon emission computed tomography (SPECT)/CT may be essential, but the procedure has still not been thoroughly evaluated. The aim of this retrospective study was to determine the effectiveness of MAA SPECT/CT in identifying digestive extrahepatic uptake, while determining potential diagnostic pitfalls. METHODS: Overall, 139 MAA SPECT/CT scans were performed on 103 patients with different hepatic tumour types. Patients were followed up for at least 6 months according to standard requirements. RESULTS: Digestive, or digestive-like, uptake other than free pertechnetate was identified in 5.7% of cases using planar imaging and in 36.6% of cases using SPECT/CT. Uptake sites identified by SPECT/CT included the gastroduodenal region (3.6%), gall bladder (12.2%), portal vein thrombosis (6.5%), hepatic artery (6.5%), coil embolization site (2.1%) as well as falciform artery (5.0%). For 2.1% of explorations, a coregistration error between SPECT and CT imaging could have led to a false diagnosis by erroneously attributing an uptake site to the stomach or gall bladder, when the uptake actually occurred in the liver. CONCLUSION: SPECT/CT is more efficacious than planar imaging in identifying digestive extrahepatic uptake sites, with extrahepatic uptake observed in one third of scans using the former procedure. However, more than half of the uptake sites in our study were vascular in nature, without therapeutic implications. The risk of coregistration errors must also be kept in mind

Guidelines for developing optical clocks with 10−1810^{-18} fractional frequency uncertainty

There has been tremendous progress in the performance of optical frequency standards since the first proposals to carry out precision spectroscopy on trapped, single ions in the 1970s. The estimated fractional frequency uncertainty of today's leading optical standards is currently in the $10^{-18}$ range, approximately two orders of magnitude better than that of the best caesium primary frequency standards. This exceptional accuracy and stability is resulting in a growing number of research groups developing optical clocks. While good review papers covering the topic already exist, more practical guidelines are needed as a complement. The purpose of this document is therefore to provide technical guidance for researchers starting in the field of optical clocks. The target audience includes national metrology institutes (NMIs) wanting to set up optical clocks (or subsystems thereof) and PhD students and postdocs entering the field. Another potential audience is academic groups with experience in atomic physics and atom or ion trapping, but with less experience of time and frequency metrology and optical clock requirements. These guidelines have arisen from the scope of the EMPIR project "Optical clocks with $1 imes 10^{-18}$ uncertainty" (OC18). Therefore, the examples are from European laboratories even though similar work is carried out all over the world. The goal of OC18 was to push the development of optical clocks by improving each of the necessary subsystems: ultrastable lasers, neutral-atom and single-ion traps, and interrogation techniques. This document shares the knowledge acquired by the OC18 project consortium and gives practical guidance on each of these aspects

A Genome-Wide Association Study Identifies rs2000999 as a Strong Genetic Determinant of Circulating Haptoglobin Levels

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far