Handheld In Vivo Reflectance Confocal Microscopy for the Diagnosis of Eyelid Margin and Conjunctival Tumors

OBJECTIVE To assess the diagnostic accuracy of handheld in vivo reflectance confocal microscopy (IVCM) for the diagnosis of eyelid margin and conjunctival tumors. DESIGN A prospective observational study was conducted at University Hospital of Saint-Etienne from January 2, 2011, to December 31, 2016 (inclusion of patients until December 31, 2015, and follow-up until December 31, 2016). A total of 278 consecutive patients with eyelid margin or conjunctival lesions were included. Conjunctival lesions were diagnosed with a conventional clinical examination using a slitlamp and by handheld IVCM. Final diagnoses were established by histopathologic examination for 155 neoformations suspicious for being malignant through clinical and/or IVCM examination that were excised and on follow-up of 12 months or longer for the remaining 140 lesions. MAIN OUTCOMES AND MEASURES Sensitivity, specificity, and positive and negative predictive values for malignant tumors of the conjunctiva and eyelid margin were calculated using clinical examination with slitlamp and handheld IVCM. RESULTS In the 278 patients (136 [48.9%] females; mean [SD] age, 59 [21] years), a total of 166 eyelid margin and 129 conjunctival lesions were included in the analysis. Of the 155 excised neoformations with a histopathologic diagnosis, IVCM showed higher sensitivity compared with clinical examination conducted with the slitlamp for malignant tumors of the eyelid margin (98%vs 92%) and conjunctiva (100% vs 88%). The specificity for malignant eyelid margin tumors was higher for IVCMthan for slitlamp examination (74%vs 46%), but slightly less for malignant conjunctival tumors (78%vs 88%). Analysis of all neoformations (155 excised and 140 in follow-up) confirmed these differences in the diagnostic accuracy of the clinical examination and IVCM. The presence of hyperreflective Langerhans cells mimicking malignant melanocytes was the main cause for misdiagnosis of malignant conjunctival tumors with IVCM. CONCLUSIONS AND RELEVANCE Handheld IVCM could be a useful tool for the identification of malignant conjunctival tumors. Further studies are required to confirm the usefulness of this device and identify possible features that can differentiate Langerhans cells from malignant melanocytes to prevent the misdiagnosis of melanoma using IVCM

Lipids modulate the conformational dynamics of a secondary multidrug transporter

Direct interactions with lipids have emerged as key determinants of the folding, structure and function of membrane proteins, but an understanding of how lipids modulate protein dynamics is still lacking. Here, we systematically explored the effects of lipids on the conformational dynamics of the proton-powered multidrug transporter LmrP from Lactococcus lactis, using the pattern of distances between spin-label pairs previously shown to report on alternating access of the protein. We uncovered, at the molecular level, how the lipid headgroups shape the conformational-energy landscape of the transporter. The model emerging from our data suggests a direct interaction between lipid headgroups and a conserved motif of charged residues that control the conformational equilibrium through an interplay of electrostatic interactions within the protein. Together, our data lay the foundation for a comprehensive model of secondary multidrug transport in lipid bilayers

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Prospects for Future Exploration of the Trans-Neptunian Region

International audienc

Seuils, Thresholds, Soglitudes

Ce numéro consacré  à l’étude de la notion de seuil ouvre le champ de la recherche pluridisciplinaire à une approche innovante et propose à la fois une lecture possible des systèmes, des notions et des textes produits par les sciences humaines et une nouvelle manière de penser, créer et produire. La notion de « soglitude » est inspirée du mot italien « soglia » qui désigne le seuil et l’état solitaire de l’homme qui ne l’est finalement pas complètement, puisque le seuil ouvre et lie, sépare et joint, arrête et situe dans le continu tout le flux de la pensée, de la perception des événements, et de la mémoire. Les textes réunis dans ce numéro proposent une première approche de la méthode de la pensée des seuils. Non seulement état-charnière, transition, le seuil est lui-même à la fois une métaphore et une réalité dans les domaines représentés ici : la photographie, le film, l’anthropologie, l’histoire, la philosophie, l’histoire de l’art et la poésie où chacun dit à sa façon comment le seuil apporte une approche plus souple, une recherche plus nuancée, un flux de la réflexion qui s’arrête seulement pour repartir sur d’autres seuils, d’autres rives. A travers des exemples parfois très concrets, les auteurs montrent que la « soglitude » est une méthode à part entière qui peut s’appliquer à des domaines de recherches très divers. Un deuxième numéro est en préparation qui se consacrera à l’application concrète de cette méthode

Duplication of 10q24 locus: broadening the clinical and radiological spectrum

International audienceSplit-hand-split-foot malformation (SHFM) is a rare condition that occurs in 1 in 8500-25,000 newborns and accounts for 15% of all limb reduction defects. SHFM is heterogeneous and can be isolated, associated with other malformations, or syndromic. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but can be X-linked or autosomal recessive. Seven loci are currently known: SHFM1 at 7q21.2q22.1 (DLX5 gene), SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27 (TP63 gene), SHFM5 at 2q31 and SHFM6 as a result of variants in WNT10B (chromosome 12q13). Duplications at 17p13.3 are seen in SHFM when isolated or associated with long bone deficiency. Tandem genomic duplications at chromosome 10q24 involving at least the DACTYLIN gene are associated with SHFM3. No point variant in any of the genes residing within the region has been identified so far, but duplication of exon 1 of the BTRC gene may explain the phenotype, with likely complex alterations of gene regulation mechanisms that would impair limb morphogenesis. We report on 32 new index cases identified by array-CGH and/or by qPCR, including some prenatal ones, leading to termination for the most severe. Twenty-two cases were presenting with SHFM and 7 with monodactyly only. Three had an overlapping phenotype. Additional findings were identified in 5 (renal dysplasia, cutis aplasia, hypogonadism and agenesis of corpus callosum with hydrocephalus). We present their clinical and radiological findings and review the literature on this rearrangement that seems to be one of the most frequent cause of SHFM

Trace Element Composition of Igneous and Hydrothermal Magnetite from Porphyry Deposits: Relationship to Deposit Subtypes and Magmatic Affinity

Trace element compositions of igneous and hydrothermal magnetite from nineteen well-studied porphyry Cu ± Au ± Mo, Mo, and W-Mo deposits, combined with partial least squares-discriminant analysis (PLS-DA), were used to investigate the factors controlling magnetite chemistry during igneous and hydrothermal processes, as divided by magmatic affinity and porphyry deposit subtypes. Igneous magnetite can be discriminated by relatively high P, Ti, V, Mn, Zr, Nb, Hf, and Ta contents but low Mg, Si, Co, Ni, Ge, Sb, W, and Pb contents, in contrast to hydrothermal magnetite. Compositional differences between igneous and hydrothermal magnetite are mainly controlled by the temperature, oxygen fugacity, co-crystallized sulfides, and element solubility/mobility that significantly affect the partition coefficients between magnetite and melt/fluids. Binary diagrams based on Ti, V, and Cr contents are not enough to discriminate igneous and hydrothermal magnetite in porphyry deposits. Relatively high Si and Al contents discriminate porphyry W-Mo hydrothermal magnetite, probably reflecting the control by high Si, highly differentiated, granitic intrusions for this deposit type. Relatively high Mg, Mn, Zr, Nb, Sn, and Hf, but low Ti and V contents, discriminate porphyry Au-Cu hydrothermal magnetite, most likely resulting from a combination of mafic to intermediate intrusion composition, high chlorine in fluids, relatively high oxygen fugacity, and low temperature conditions. Igneous or hydrothermal magnetite from Cu-Mo, Cu-Au, and Cu-Mo-Au deposits cannot be discriminated from each other probably due to similar intermediate to felsic intrusion composition, melt/fluid composition, and conditions such as temperature and oxygen fugacity for the formation of these deposits. The magmatic affinity of porphyritic intrusions exerts some control on the chemical composition of igneous and hydrothermal magnetite in porphyry system. Igneous and hydrothermal magnetite related to alkaline magma is relatively rich in Mg, Mn, Co, Mo, Sn, and high field strength elements (HFSE), perhaps due to high concentrations of chlorine and fluorine in magma and exsolved fluids, whereas those related to calc-alkaline magma are relatively rich in Ca but depleted in HFSE, consistent with the high Ca but low HFSE magma composition. Igneous and hydrothermal magnetite related to high-K calc-alkaline magma is relatively rich in Al, Ti, Sc, and Ta, due to a higher temperature of formation or enrichment of these elements in melt/fluids. PLS-DA on hydrothermal magnetite compositions from worldwide porphyry Cu, iron oxide-copper-gold (IOCG), Kiruna-type iron oxide-apatite (IOA), and skarn deposits identify important discriminant elements for these deposit types. Magnetite from porphyry Cu deposits is characterized by relatively high Ti, V, Zn, and Al contents, whereas that from IOCG deposits can be discriminated from other types of magnetite by its relatively high V, Ni, Ti, and Al contents. IOA magnetite is discriminated by higher V, Ti, and Mg but lower Al contents, whereas skarn magnetite can be separated from magnetite from other deposit types by higher Mn, Mg, Ca, and Zn contents. Decreased Ti and V contents in hydrothermal magnetite from porphyry Cu and IOA, to IOCG, and to skarn deposits may be related to decreasing temperature and increasing oxygen fugacity. The relative depletion of Al in IOA magnetite is due to its low magnetite-silicate melt partition coefficient, immobility of Al in fluids, and earlier, higher-temperature magmatic or magmatic-hydrothermal formation of IOA deposits. The relative enrichment of Ni in IOCG magnetite reflects more mafic magmatic composition and less competition with sulfide, whereas elevated Mn, Mg, Ca, and Zn in skarn magnetite results from enrichment of these elements in fluids via more intensive fluid-carbonate rock interaction

Additional file 8 of Worldwide clinical practices in perioperative antibiotic therapy for lung transplantation

Additional file 8 Answers according to large et small volume centers. The groups were defined on the median of lung transplants performed in 2017 (n = 28). LTx: lung transplantation