p4EBP1 staining predicts outcome in ER-positive endocrine-resistant metastatic breast cancer patients treated with everolimus and exemestane.

BACKGROUND: To identify patients most likely to respond to everolimus, a mammalian target of rapamycin (mTOR) inhibitor, a prospective biomarker study was conducted in hormone receptor-positive endocrine-resistant metastatic breast cancer patients treated with exemestane-everolimus therapy. METHODS: Metastatic tumor biopsies were processed for immunohistochemical staining (p4EBP1, PTEN, pAKT, LKB1, and pS6K). ESR1, PIK3CA and AKT1 gene mutations were detected by NGS. The primary endpoint was the association between the p4EBP1 expression and clinical benefit rate (CBR) at 6 months of everolimus plus exemestane treatment. RESULTS: Of 150 patients included, 107 were evaluable for the primary endpoint. p4EBP1 staining above the median (Allred score ≥6) was associated with a higher CBR at 6 months (62% versus 40% in high-p4EBP1 versus low-p4EBP1, χ2 test, p = 0.026) and a longer progression-free survival (PFS) (median PFS of 9.2 versus 5.8 months in high-p4EBP1 versus low-p4EBP1; p = 0.02). When tested with other biomarkers, only p4EBP1 remained a significant predictive marker of PFS in multivariate analysis (hazard ratio, 0.591; p = 0.01). CONCLUSIONS: This study identified a subset of patients with hormone receptor-positive endocrine-resistant metastatic breast cancer and poor outcome who would derive less benefit from everolimus and exemestane. p4EBP1 may be a useful predictive biomarker in routine clinical practice. CLINICAL TRIAL REGISTRATION: NCT02444390.

Human dendritic cell maturation induced by amorphous silica nanoparticles is Syk-dependent and triggered by lipid raft aggregation.

BACKGROUND: Synthetic amorphous silica nanoparticles (SAS-NPs) are widely employed in pharmaceutics, cosmetics, food and concretes. Workers and the general population are exposed daily via diverse routes of exposure. SAS-NPs are generally recognized as safe (GRAS) by the Food and Drug Administration, but because of their nanoscale size and extensive uses, a better assessment of their immunotoxicity is required. In the presence of immune "danger signals", dendritic cells (DCs) undergo a maturation process resulting in their migration to regional lymph nodes where they activate naive T-cells. We have previously shown that fumed silica pyrogenic SAS-NPs promote the two first steps of the adaptative immune response by triggering DC maturation and T-lymphocyte response, suggesting that SAS-NPs could behave as immune "danger signals". The present work aims to identify the mechanism and the signalling pathways involved in DC phenotype modifications provoked by pyrogenic SAS-NPs. As a pivotal intracellular signalling molecule whose phosphorylation is associated with DC maturation, we hypothesized that Spleen tyrosine kinase (Syk) may play a central role in SAS-NPs-induced DC response. RESULTS: In human monocyte-derived dendritic cells (moDCs) exposed to SAS-NPs, Syk inhibition prevented the induction of CD83 and CD86 marker expression. A significant decrease in T-cell proliferation and IFN-γ, IL-17F and IL-9 production was found in an allogeneic moDC:T-cell co-culture model. These results suggested that the activation of Syk was necessary for optimal co-stimulation of T-cells. Moreover, Syk phosphorylation, observed 30 min after SAS-NP exposure, occurred upstream of the c-Jun N-terminal kinase (JNK) Mitogen-activated protein kinases (MAPK) and was elicited by the Src family of protein tyrosine kinases. Our results also showed for the first time that SAS-NPs provoked aggregation of lipid rafts in moDCs and that MßCD-mediated raft destabilisation altered Syk activation. CONCLUSIONS: We showed that SAS-NPs could act as an immune danger signal in DCs through a Syk-dependent pathway. Our findings revealed an original mechanism whereby the interaction of SAS-NPs with DC membranes promoted aggregation of lipid rafts, leading to a Src kinase-initiated activation loop triggering Syk activation and functional DC maturation.

The FcγRIIa-Syk Axis Controls Human Dendritic Cell Activation and T Cell Response Induced by Infliximab Aggregates.

The development of anti-drug Abs in response to biological products (BP) is a major drawback in the treatment of patients. Factors related to the patient, the treatment, and the product can influence BP immunogenicity. Among these factors, BP aggregates have been suggested to promote immunogenicity by acting as danger signals recognized by dendritic cells (DC) facilitating the establishment of an anti-BP CD4 T cell-dependent adaptive immune response leading to anti-drug Abs production. To date, little is known on the mechanism supporting the effect of aggregates on DCs and consequently on the T cell response. The aim of this work was to identify key signaling pathways involved in BP aggregate DC activation and T cell response. We generated aggregates by submitting infliximab (IFX), an immunogenic anti-TNF-α chimeric Ab, to heat stress. Our results showed that IFX aggregates were able to induce human monocyte-derived DC (moDC) maturation in a concentration-dependent manner. Aggregate-treated moDCs enhanced allogeneic T cell proliferation and IL-5, IL-9, and IL-13 production compared with native Ab-treated moDCs. We then investigated the implication of FcγRIIa and spleen tyrosine kinase (Syk) in DC activation and showed that they were both strongly implicated in moDC maturation induced by IFX aggregates. Indeed, we found that neutralization of FcγRIIa inhibited DC activation, and consequently, Syk inhibition led to a decrease in T cell proliferation and cytokine production in response to IFX aggregates. Taken together, our results bring new insight, to our knowledge, on how protein aggregates could induce DC and T cell activation via the FcγRIIa-Syk signaling pathway.

Discriminative and quantitative analysis of norepinephrine and epinephrine by surface-enhanced Raman spectroscopy with gold nanoparticle suspensions.

Surface-enhanced Raman spectroscopy (SERS) is a powerful analytical technique capable of increasing the Raman signal of an analyte using specific nanostructures. The close contact between those nanostructures, usually a suspension of nanoparticles, and the molecule of interest produces an important exaltation of the intensity of the Raman signal. Even if the exaltation leads to an improvement of Raman spectroscopy sensitivity, the complexity of the SERS signal and the numbers of parameters to be controlled allow the use of SERS for detection rather than quantification. The aim of this study was to develop a robust discriminative and quantitative analysis in accordance with pharmaceutical standards. In this present work, we develop a discriminative and quantitative analysis based on the previous optimized parameters obtained by the design of experiments fixed for norepinephrine (NOR) and extended to epinephrine (EPI) which are two neurotransmitters with very similar structures. Studying the short evolution of the Raman signal intensity over time coupled with chemometric tools allowed the identification of outliers and their removal from the data set. The discriminant analysis showed an excellent separation of EPI and NOR. The comparative analysis of the data showed the superiority of the multivariate analysis after logarithmic transformation. The quantitative analysis allowed the development of robust quantification models from several gold nanoparticle batches with limits of quantification of 32 µg/mL for NOR and below 20 µg/mL for EPI even though no Raman signal is observable for such concentrations. This study improves SERS analysis over ultrasensitive detection for discrimination and quantification using a handheld Raman spectrometer.

Effect of growth hormone and IgG aggregates on dendritic cells activation and T-cells polarization.

Patients treated with therapeutic biological products (BP) frequently develop anti-drug antibodies (ADA) with potential neutralizing capacities leading to loss of clinical response or serious side effects. BP aggregates have been suggested to promote immunogenicity, thus enhancing ADA production. Dendritic cells (DC) are key effectors in T-cell and B-cell fates, and the subsequent generation of immunogenicity. The objective of this work was to determine if BP aggregates can participate to DC maturation and T-cell activation. We compared aggregates from three different proteins: human growth hormone (hGH), Rituximab, a chimeric anti-CD20 antibody and a serum-purified human IgG1. All three proteins underwent a stir stress, generating comparable populations of aggregated particles. Maturation of human monocyte-derived DC (moDC) upon exposure to native BPs or aggregates was evaluated in vitro. Results showed that hGH aggregates induced an increased expression of moDC co-stimulation markers, and augmented levels of IL-6, IL-8, IL-12p40, CCL2, CCL3, CCL4 and CXCL10. Both antibodies aggregates were also able to modify DC phenotype, but cytokine and chemokine productions were seen only with IL-6, IL-8, IL-12p40 and CXCL10. Aggregates-treated moDC enhanced allogenic T-cell proliferation and cytokines production, suggesting Th1 polarization with hGH, and mixed T-cell responses with antibodies aggregates. These results showed that BP aggregates provoked DC maturation, thus driving adaptive T-cell responses and polarization.

Self-Assembly of Amphiphilic Biotransesterified ß-Cyclodextrins: Supramolecular Structure of Nanoparticles and Surface Properties.

A series of ß-cyclodextrin (ßCD) amphiphilic derivatives with varying degrees of substitution were prepared by acylating ßCDs on their secondary face using thermolysin to catalyze the transesterification. After dissolution in acetone, the ßCD-Cn derivatives (n = 8, 10, 12, 14) were nanoprecipitated in water, where they self-organized into structured particles that were characterized using cryo-transmission electron microscopy (cryo-TEM) images and small-angle X-ray scattering (SAXS) data. Two types of morphologies and ultrastructures were observed depending on the total degree of substitution (TDS) of the parent derivative. The molecules with TDS < 5 formed nanospheres with a multilamellar organization, whereas those with TDS > 5 self-assembled into barrel-like (n = 8, 10, 12) or more tortuous (n = 14) particles with a columnar inverse hexagonal structure. In particular, faceted ßCD-C14 particles (TDS = 7) appeared to be composed of several domains with different orientations that were separated by sharp interfaces. Ultrastructural models were proposed on the basis of cryo-TEM images and the analysis of the contrast distribution in different projections of the lattice. Complementary compression isotherm experiments carried out at the air-water interface also suggested that differences in the molecular conformation of the series of derivatives existed depending on whether TDS was lower or higher than 5.

Single-Scan Multidimensional NMR Analysis of Mixtures at Sub-Millimolar Concentrations by using SABRE Hyperpolarization.

Signal amplification by reversible exchange (SABRE) is a promising method to increase the sensitivity of nuclear magnetic resonance (NMR) experiments. However, SABRE-enhanced (1)H NMR signals are short lived, and SABRE is often used to record 1D NMR spectra only. When the sample of interest is a complex mixture, this results in severe overlaps for (1)H spectra. In addition, the use of a co-substrate, whose signals may obscure the (1) H spectra, is currently the most efficient way to lower the detection limit of SABRE experiments. Here, we describe an approach to obtain clean, SABRE-hyperpolarized 2D (1)H NMR spectra of mixtures of small molecules at sub-millimolar concentrations in a single scan. The method relies on the use of para-hydrogen together with a deuterated co-substrate for hyperpolarization and ultrafast 2D NMR for acquisition. It is applicable to all substrates that can be polarized with SABRE.

Development of nanoparticles based on amphiphilic cyclodextrins for the delivery of active substances.

Although amphiphilic cyclodextrin derivatives (ACDs) serve as valuable building blocks for nanomedicine formulations, their widespread production still encounters various challenges, limiting large-scale manufacturing. This work focuses on a robust alternative pathway using mineral base catalysis to transesterify ß-cyclodextrin with long-chain vinyl esters, yielding ACD with modular and controlled hydrocarbon chain grafting. ACDs with a wide range of degrees of substitution (DS) were reliably synthesized, as indicated by extensive physicochemical characterization, including MALDI-TOF mass spectrometry. The influence of various factors, including the type of catalyst and the length of the hydrocarbon moiety of the vinyl ester, was studied in detail. ACDs were assessed for their ability to form colloidal suspensions by nanoprecipitation, with or without PEGylated phospholipid. Small-angle X-ray scattering and cryo-electron microscopy revealed the formation of nanoparticles with distinct ultrastructures depending on the DS: an onion-like structure for low and very high DS, and reversed hexagonal organization for DS between 4.5 and 6.1. We confirmed the furtivity of the PEGylated versions of the nanoparticles through complement activation experiments and that they were well tolerated in-vivo on a zebrafish larvae model after intravenous injection. Furthermore, a biodistribution experiment showed that the nanoparticles left the bloodstream within 10 h after injection and were phagocytosed by macrophages.

Fragmentation of DMPC Membranes by a Wedge-Shaped Amphiphilic Cyclodextrin into Bicellar-like Aggregates.

Small bilayer lipid aggregates such as bicelles provide useful isotropic or anisotropic membrane mimetics for structural studies of biological membranes. We have shown previously by deuterium NMR that a wedge-shaped amphiphilic derivative of trimethyl ßcyclodextrin anchored in deuterated DMPC-d27 bilayers through a lauryl acyl chain (TrimßMLC) is able to induce magnetic orientation and fragmentation of the multilamellar membranes. The fragmentation process fully detailed in the present paper is observed with 20% cyclodextrin derivative below 37 °C, where pure TrimßMLC self-assembles in water into large giant micellar structures. After deconvolution of a broad composite 2H NMR isotropic component, we propose a model where the DMPC membranes are progressively disrupted by TrimßMLC into small and large micellar aggregates depending whether they are extracted from the outer or inner layers of the liposomes. Below the fluid-to-gel transition of pure DMPC-d27 membranes (Tc = 21.5 °C), the micellar aggregates vanish progressively until complete extinction at 13 °C, with a probable release of pure TrimßMLC micelles leaving lipid bilayers in the gel phase doped with only a small amount of the cyclodextrin derivative. Bilayer fragmentation between Tc and 13 °C was also observed with 10% and 5% of TrimßMLC, with NMR spectra suggesting possible interactions of micellar aggregates with fluid-like lipids of the Pß' ripple phase. No membrane orientation and fragmentation was detected with unsaturated POPC membranes, which are able to accommodate the insertion of TrimßMLC without important perturbation. The data are discussed in relation to the formation of possible DMPC bicellar aggregates such as those known to occur after insertion of dihexanoylphosphatidylcholine (DHPC). These bicelles are in particular associated with similar deuterium NMR spectra exhibiting identical composite isotropic components which were never characterized before.

Automatic uncertainty-based quality controlled T1 mapping and ECV analysis from native and post-contrast cardiac T1 mapping images using Bayesian vision transformer.

Deep learning-based methods for cardiac MR segmentation have achieved state-of-the-art results. However, these methods can generate incorrect segmentation results which can lead to wrong clinical decisions in the downstream tasks. Automatic and accurate analysis of downstream tasks, such as myocardial tissue characterization, is highly dependent on the quality of the segmentation results. Therefore, it is of paramount importance to use quality control methods to detect the failed segmentations before further analysis. In this work, we propose a fully automatic uncertainty-based quality control framework for T1 mapping and extracellular volume (ECV) analysis. The framework consists of three parts. The first one focuses on segmentation of cardiac structures from a native and post-contrast T1 mapping dataset (n=295) using a Bayesian Swin transformer-based U-Net. In the second part, we propose a novel uncertainty-based quality control (QC) to detect inaccurate segmentation results. The QC method utilizes image-level uncertainty features as input to a random forest-based classifier/regressor to determine the quality of the segmentation outputs. The experimental results from four different types of segmentation results show that the proposed QC method achieves a mean area under the ROC curve (AUC) of 0.927 on binary classification and a mean absolute error (MAE) of 0.021 on Dice score regression, significantly outperforming other state-of-the-art uncertainty based QC methods. The performance gap is notably higher in predicting the segmentation quality from poor-performing models which shows the robustness of our method in detecting failed segmentations. After the inaccurate segmentation results are detected and rejected by the QC method, in the third part, T1 mapping and ECV values are computed automatically to characterize the myocardial tissues of healthy and cardiac pathological cases. The native myocardial T1 and ECV values computed from automatic and manual segmentations show an excellent agreement yielding Pearson coefficients of 0.990 and 0.975 (on the combined validation and test sets), respectively. From the results, we observe that the automatically computed myocardial T1 and ECV values have the ability to characterize myocardial tissues of healthy and cardiac diseases like myocardial infarction, amyloidosis, Tako-Tsubo syndrome, dilated cardiomyopathy, and hypertrophic cardiomyopathy.

Molecular Mechanisms Involved in the Chemical Instability of ONC201 and Methods to Counter Its Degradation in Solution.

Glioblastoma is one of the most common and aggressive forms of brain tumor, a rare disease for which there is a great need for innovative therapies. ONC201, a new drug substance, has been used in a compassionate treatment program where the choice of dosage form and regimen have yet to be justified. The prior knowledge needed to anticipate ONC201 stability problems has recently been partially addressed, by (i) showing that ONC201 is sensitive to light and oxidation and (ii) identifying the molecular structures of the main degradation products formed. The aim of the work presented here was to improve our understanding of the degradation pathways of ONC201 using data from ab initio calculations and experimental work to supplement the structural information we already published. The C-H bonds located αto the amine of the tetrahydropyridine group and those located alpha to the imine function of the dihydroimidazole group exhibit the lowest bond dissociation energies (BDEs) within the ONC201 molecule. Moreover, these values drop well below 90 kcal.mol-1 when ONC201 is in an excited state (S1; T1). The structures of the photoproducts we had previously identified are consistent with these data, showing that they would have resulted from radical processes following the abstraction of alpha hydrogens. Concerning ONC201's sensitivity to oxidation, the structures of the oxidation products matched the critical points revealed through mapped electrostatic potential (MEP) and average local ionization energy (ALIE). The data obtained from ab initio calculations and experimental work showed that the reactivity of ONC201 to light and oxidation conditions is highly dependent on pH. While an acidic environment (pH < 6) contributes to making ONC201 quantitatively more stable in solution in the face of oxidation and photo-oxidation, it nevertheless seems that certain chemical groups in the molecule are more exposed to nucleophilic attacks, which explains the variation observed in the profile of degradation products formed in the presence of certain antioxidants tested. This information is crucial to better understand the stability results in the presence of antioxidant agents and to determine the right conditions for them to act.

Optimization of experimental conditions by surface enhanced Raman Scattering (SERS) spectroscopy with gold nanoparticles suspensions.

Surface Enhanced Raman Scattering (SERS) spectroscopy is a rapid and innovative analysis technique involving metallic nanoparticles (NPs). The interaction between NPs and norepinephrine gives an exaltation of the Raman signal under certain experimental conditions. The control of the signal exaltation, crucial for sensitive analyses, remains one of the main limitations of this technique. The aim of this work is to optimize the exaltation conditions for an optimal SERS signal at two concentrations of norepinephrine (NOR) and spherical gold NPs in suspension. This first work will fix the optimal experimental conditions essential for the development of robust discriminant and quantitative analysis of catecholamine. Two complete 3-factors 3-levels experiment designs were performed at 20 µg.mL-1 and 100 µg.mL-1 norepinephrine concentrations, each experiment being repeated 3 times. The optimization factors were the process of synthesis (variation of the quantity of gold and citrate used for the three synthesis SA, SB and SC) and HCl (0.3 M, 0.5 M, 0.7 M) as well as the volume ratio of NPs and norepinephrine (0.5, 2, 3.5) for SERS acquisition. Spectral acquisitions were performed with a handheld Raman spectrometer with an excitation source at 785 nm. For each sample, 31 acquisitions were realized during 3 s every 8 s. The optimization parameter was the intensity of the characteristic band of norepinephrine at 1280 cm-1. A total of 5,042 spectra were acquired and the pre-treatment selected for all spectra was asymmetric least square combined to a smoothing of Savistsky Golay (ALS - SG). The optimal contact time between norepinephrine and NPs depends on the experimental conditions and was determined for each experiment according to the mean intensity between the three replicates. After interpretation of the experimental designs, the optimal conditions retained were the quantity of gold corresponding to SA and the HCl concentration 0.7 M for the two concentrations of norepinephrine. Indeed, the optimal volume ratio depend on the NOR concentration.

Breaking photoswitch activation depth limit using ionising radiation stimuli adapted to clinical application.

Electromagnetic radiation-triggered therapeutic effect has attracted a great interest over the last 50 years. However, translation to clinical applications of photoactive molecular systems developed to date is dramatically limited, mainly because their activation requires excitation by low-energy photons from the ultraviolet to near infra-red range, preventing any activation deeper than few millimetres under the skin. Herein we conceive a strategy for photosensitive-system activation potentially adapted to biological tissues without any restriction in depth. High-energy stimuli, such as those employed for radiotherapy, are used to carry energy while molecular activation is provided by local energy conversion. This concept is applied to azobenzene, one of the most established photoswitches, to build a radioswitch. The radiation-responsive molecular system developed is used to trigger cytotoxic effect on cancer cells upon gamma-ray irradiation. This breakthrough activation concept is expected to expand the scope of applications of photosensitive systems and paves the way towards the development of original therapeutic approaches.

Cochleate drug delivery systems: An approach to their characterization.

Cochleate systems formed from phospholipids have very useful properties as drug delivery systems with sustained release capabilities, which are able to improve bioavailability and efficacy, reduce toxicity and increase the shelf-life of encapsulated molecules. These nanometric or micrometric structures are usually obtained after interaction of negatively charged liposomes with a positively charged bridging agent. Many different methods are now available to prepare cochleates and there are also numerous techniques that can be used to characterize them, some of which can be easily applied while others require more sophisticated equipment or analysis. The present review describes the important features of this drug delivery system; including their structural properties and potential applications, as well as a brief account of methods for their preparation and an extensive description of the techniques used for their characterization. This information could guide formulators in their choice of methods of characterization that would be best suited to their needs in terms of time, precision and technological difficulty.

Cloaking, trapping and superlensing of lamb waves with negative refraction.

We report on experimental and numerical implementations of devices based on the negative refraction of elastic guided waves, the so-called Lamb waves. Consisting in plates of varying thickness, these devices rely on the concept of complementary media, where a particular layout of negative index media can cloak an object with its anti-object or trap waves around a negative corner. The diffraction cancellation operated by negative refraction is investigated by means of laser ultrasound experiments. However, unlike original theoretical predictions, these intriguing wave phenomena remain, nevertheless, limited to the propagating component of the wave-field. To go beyond the diffraction limit, negative refraction is combined with the concept of metalens, a device converting the evanescent components of an object into propagating waves. The transport of an evanescent wave-field is then possible from an object plane to a far-field imaging plane. Twenty years after Pendry's initial proposal, this work thus paves the way towards an elastic superlens.

Synthetic Amorphous Silica Nanoparticles Promote Human Dendritic Cell Maturation and CD4+ T-Lymphocyte Activation.

Innate immune cells such as dendritic cells (DCs) sense and engulf nanomaterials potentially leading to an adverse immune response. Indeed, as described for combustion-derived particles, nanomaterials could be sensed as danger signals, enabling DCs to undergo a maturation process, migrate to regional lymph nodes and activate naive T lymphocytes. Synthetic amorphous silica nanoparticles (SAS-NPs) are widely used as food additives, cosmetics, and construction materials. This work aimed to evaluate in vitro the effects of manufactured SAS-NPs, produced by thermal or wet routes, on human DCs functions and T-cell activation. Human monocyte-derived DCs (moDCs) were exposed for 16 h to 3 endotoxin-free test materials: fumed silica NPs from Sigma-Aldrich (no. S5505) or the JRC Nanomaterial Repository (NM-202) and colloidal LudoxTMA NPs. Cell viability, phenotypical changes, cytokines production, internalization, and allogeneic CD4+ T-cells proliferation were evaluated. Our results showed that all SAS-NPs significantly upregulated the surface expression of CD86 and CD83 activation markers. Secretions of pro-inflammatory cytokines (CXCL-8 and CXCL-12) were significantly enhanced in a dose-dependent manner in the moDCs culture supernatants by all SAS-NPs tested. In an allogeneic coculture, fumed silica-activated moDCs significantly increased T-lymphocyte proliferation at all T-cell: DC ratios compared with unloaded moDCs. Moreover, analysis of coculture supernatants regarding the production of T-cell-derived cytokines showed a significant increase of IL-9 and IL-17A and F, as well as an upregulation of IL-5, consistent with the pro-inflammatory phenotype of treated moDCs. Taken together, these results suggest that SAS-NPs could induce functional moDCs maturation and play a role in the immunization process against environmental antigens.

Double Loop Ureteral Stent Encrustation According to Indwelling Time: Results of a European Multicentric Study.

Introduction: Double-J ureteral stents are subject to encrustation. Studies have shown that the encrustation onset is linked with indwelling time. In prevention, it is admitted that the Double-J stent indwelt for medium or long term should be replaced periodically. However, in the absence of guidelines, indwelling durations vary with centers' habits, stent indication, and stent materials. Our target was to evaluate the actual ureteral stent medium-/long-term indwelling times and related encrustation rates perceived by urologists in daily practice. Methods: An observational retrospective study was performed over six European centers. All data of all consecutive removed stents of the same material implanted for more than 2 months within a same 2-year referred period were collected. Three stent types of various materials, with/without coating, were evaluated. Encrustation rates were analyzed according to indwelling times and stent indication. Results: Four hundred seventy-three stents were recorded with indwelling times between 60 and 679 days. An unexpected number of long-term indwelling times were noticed: globally one-third more than 6 months, and 9% more than 1 year. In case of malignant indication, these rates were, respectively, 44% and 17%. For nonstone indication, clinically significant encrustation rates stayed extremely low before 4 months (1.3%) and quite low before 6 months (5.2%), increasing with time to reach around 10% in the long term. However, as expected, the rate was higher for stone indication with a marked increase after 4 months (8% before 4 months, nearly 17% after). Conclusion: Our data confirm a higher encrustation risk for stone patients. Long indwelling times in nonstone patients beyond 6 months or even 12 months appear to be still requested and relatively well supported in usual practice by this population.

Tuning morphology of Pickering emulsions stabilised by biodegradable PLGA nanoparticles: How PLGA characteristics influence emulsion properties.

In this study, we proved that the stabilisation of Pickering emulsions by polymer nanoparticles (NPs) heavily depends on polymer characteristics. We prepared NPs with four poly(lactide-co-glycolide) polymers (PLGA), of different molar masses (14,000 and 32,000 g/mol) and end groups (acid or alkylester). NPs were either bare (without stabilising polymer) or covered by polyvinyl alcohol (PVA). Pickering emulsions were prepared by mixing NP aqueous suspensions with various amounts of oil (Miglyol 812 N). First, NP wettability was directly affected by PLGA end group: ester-ending PLGA led to more hydrophobic NPs, compared to acid-ending PLGA. This effect of the end group could be slightly enhanced with smaller molar mass. Thus, bare PLGA NPs stabilised different types of emulsions (W/O/W and W/O), following Finkle's rule. However, the effect of PLGA characteristics was masked when NPs were covered by PVA, as PVA drove the stabilisation of O/W emulsions. Secondly, PLGA molar mass and end group also influenced its glass transition temperature (Tg), with spectacular consequences on emulsion formation. Indeed, the shortest ester-ending PLGA exhibited a Tg close to room temperature, when measured in the emulsion. This Tg, easily exceeded during emulsification process, led to a soft solid emulsion, stabilised by a network of NP debris.

New phosphane based on a beta-cyclodextrin, exhibiting a solvent-tunable conformation, and its catalytic properties.

A new diphenylphosphane based on a beta-cyclodextrin skeleton that exhibits a dual solubility in water and in organic solvent was synthesised. Interestingly, a solvent-dependent conformation change was evidenced by NMR spectroscopy studies; the self-inclusion of a phenyl group of the phosphane moiety into cyclodextrin cavity observed in water disappeared in organic solvents due to a change in conformation. Hydrogenation or hydroformylation reactions performed in water and in organic solvents showed that this ligand was able to stabilise catalytically active rhodium species in solution. In the case of the hydroformylation reaction, it was demonstrated that regioselectivity was influenced by the solvent-dependent conformation of the ligand.

How to Address the Adjuvant Effects of Nanoparticles on the Immune System.

As the nanotechnology market expands and the prevalence of allergic diseases keeps increasing, the knowledge gap on the capacity of nanomaterials to cause or exacerbate allergic outcomes needs more than ever to be filled. Engineered nanoparticles (NP) could have an adjuvant effect on the immune system as previously demonstrated for particulate air pollution. This effect would be the consequence of the recognition of NP as immune danger signals by dendritic cells (DCs). The aim of this work was to set up an in vitro method to functionally assess this effect using amorphous silica NP as a prototype. Most studies in this field are restricted to the evaluation of DCs maturation, generally of murine origin, through a limited phenotypic analysis. As it is essential to also consider the functional consequences of NP-induced DC altered phenotype on T-cells biology, we developed an allogeneic co-culture model of human monocyte-derived DCs (MoDCs) and CD4+ T-cells. We demonstrated that DC: T-cell ratios were a critical parameter to correctly measure the influence of NP danger signals through allogeneic co-culture. Moreover, to better visualize the effect of NP while minimizing the basal proliferation inherent to the model, we recommend testing three different ratios, preferably after five days of co-culture.