Epidermal Growth Factor Receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer

<p>Abstract</p> <p>Background</p> <p>Activating mutations of the epidermal growth factor receptor (<it>EGFR</it>) confer sensitivity to the tyrosine kinase inhibitors (TKi), gefitinib and erlotinib. We analysed EGFR expression, EGFR mutation status and gene expression profiles of prostate cancer (PC) to supply a rationale for EGFR targeted therapies in this disease.</p> <p>Methods</p> <p>Mutational analysis of EGFR TK domain (exons from 18 to 21) and immunohistochemistry for EGFR were performed on tumour tissues derived from radical prostatectomy from 100 PC patients. Gene expression profiling using oligo-microarrays was also carried out in 51 of the PC samples.</p> <p>Results</p> <p>EGFR protein overexpression (EGFR_high) was found in 36% of the tumour samples, and mutations were found in 13% of samples. Patients with EGFR_hightumours experienced a significantly increased risk of biochemical relapse (hazard ratio-HR 2.52, p=0.02) compared with patients with tumours expressing low levels of EGFR (EGFR_low). Microarray analysis did not reveal any differences in gene expression between EGFR_highand EGFR_lowtumours. Conversely, in EGFR_hightumours, we were able to identify a 79 gene signature distinguishing mutated from non-mutated tumours. Additionally, 29 genes were found to be differentially expressed between mutated/EGFR_high(n=3) and mutated/EGFR_lowtumours (n=5). Four of the down-regulated genes, U19/EAF2, ABCC4, KLK3 and ANXA3 and one of the up-regulated genes, FOXC1, are involved in PC progression.</p> <p>Conclusions</p> <p>Based on our findings, we hypothesize that accurate definition of the EGFR status could improve prognostic stratification and we suggest a possible role for EGFR-directed therapies in PC patients. Having been generated in a relatively small sample of patients, our results warrant confirmation in larger series.</p

Integration of modeling and simulation into hospital-based decision support systems guiding pediatric pharmacotherapy

<p>Abstract</p> <p>Background</p> <p>Decision analysis in hospital-based settings is becoming more common place. The application of modeling and simulation approaches has likewise become more prevalent in order to support decision analytics. With respect to clinical decision making at the level of the patient, modeling and simulation approaches have been used to study and forecast treatment options, examine and rate caregiver performance and assign resources (staffing, beds, patient throughput). There us a great need to facilitate pharmacotherapeutic decision making in pediatrics given the often limited data available to guide dosing and manage patient response. We have employed nonlinear mixed effect models and Bayesian forecasting algorithms coupled with data summary and visualization tools to create drug-specific decision support systems that utilize individualized patient data from our electronic medical records systems.</p> <p>Methods</p> <p>Pharmacokinetic and pharmacodynamic nonlinear mixed-effect models of specific drugs are generated based on historical data in relevant pediatric populations or from adults when no pediatric data is available. These models are re-executed with individual patient data allowing for patient-specific guidance via a Bayesian forecasting approach. The models are called and executed in an interactive manner through our web-based dashboard environment which interfaces to the hospital's electronic medical records system.</p> <p>Results</p> <p>The methotrexate dashboard utilizes a two-compartment, population-based, PK mixed-effect model to project patient response to specific dosing events. Projected plasma concentrations are viewable against protocol-specific nomograms to provide dosing guidance for potential rescue therapy with leucovorin. These data are also viewable against common biomarkers used to assess patient safety (e.g., vital signs and plasma creatinine levels). As additional data become available via therapeutic drug monitoring, the model is re-executed and projections are revised.</p> <p>Conclusion</p> <p>The management of pediatric pharmacotherapy can be greatly enhanced via the immediate feedback provided by decision analytics which incorporate the current, best-available knowledge pertaining to dose-exposure and exposure-response relationships, especially for narrow therapeutic agents that are difficult to manage.</p

Overlap and Mutual Distinctions between Clinical Recovery and Personal Recovery in People with Schizophrenia in a One-Year Study

Recovery is a multidimensional construct that can be defined either from a clinical perspective or from a consumer-focused one, as a self-broadening process aimed at living a meaningful life beyond mental illness. We aimed to longitudinally examine the overlap and mutual distinctions between clinical and personal recovery. Of 1239 people with schizophrenia consecutively recruited from the FondaMental Advanced Centers of Expertise for SZ network, the 507 present at one-year did not differ from those lost to follow-up. Clinical recovery was defined as the combination of clinical remission and functional remission. Personal recovery was defined as being in the rebuilding or in the growth stage of the Stages of Recovery Instrument (STORI). Full recovery was defined as the combination of clinical recovery and personal recovery. First, we examined the factors at baseline associated with each aspect of recovery. Then, we conducted multivariable models on the correlates of stable clinical recovery, stable personal recovery, and stable full recovery after one year. At baseline, clinical recovery and personal recovery were characterized by distinct patterns of outcome (i.e. better objective outcomes but no difference in subjective outcomes for clinical recovery, the opposite pattern for personal recovery, and better overall outcomes for full recovery). We found that clinical recovery and personal recovery predicted each other over time (baseline personal recovery for stable clinical recovery at one year; P =. 026, OR = 4.94 [1.30-23.0]; baseline clinical recovery for stable personal recovery at one year; P =. 016, OR = 3.64 [1.31-11.2]). In short, given the interaction but also the degree of difference between clinical recovery and personal recovery, psychosocial treatment should target, beyond clinical recovery, subjective aspects such as personal recovery and depression to reach full recovery. © 2021 The Author(s). Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.Sorbonne Universités à Paris pour l'Enseignement et la RechercheFondaMental-Cohorte

Schizophrenia Bulletin Open

Treatment-resistant schizophrenia (TRS) affects around 30% of patients with schizophrenia (SZ) resulting in poor functioning, relapses, and reduced quality of life. Convergent findings show that inflammation could contribute to resistance. We thus search for immune signatures of patients with TRS/ultra TRS (UTRS) in a sample of community-dwelling outpatients with SZ. In total, 195 stabilized SZ patients (mean age = 31.2 years, 73% male gender) were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia in France and received a thorough clinical assessment. At inclusion, psychotic symptomatology was evaluated by the Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Circulating serum/plasma levels of a large panel of markers reflecting the main inflammatory pathways were evaluated. TRS was defined by current treatment by clozapine (CLZ) and UTRS by current CLZ treatment + PANSS total score ≥ 70. The frequency of TRS and UTRS patients was, respectively, 20% and 7.7% and was defined using multivariable analysis elevated by high levels of interleukin (IL)-12/IL-23p40, IL-17A, IL-10, and beta 2 microglobulin (B2M) and IL-12/IL-23p40, IL-17A, IL-6, IL-10, IFNγ, and B2M, respectively. These observations suggest that resistance and ultra resistance to CLZ treatment are underpinned by pro-inflammatory molecules mainly belonging to the T helper 17 pathway, a finding making sense given the interplay between inflammation and antipsychotic treatment responses. If confirmed, our findings may allow us to consider IL-23/IL-17 pathway as a therapeutic target for patients with resistance to antipsychotics.Sorbonne Universités à Paris pour l'Enseignement et la RechercheFondaMental-Cohorte

Immuno-metabolic profile of patients with psychotic disorders and metabolic syndrome. Results from the FACE-SZ cohort

Background: Metabolic syndrome (MetS) is a highly prevalent and harmful medical disorder often comorbid with psychosis where it can contribute to cardiovascular complications. As immune dysfunction is a key shared component of both MetS and schizophrenia (SZ), this study investigated the relationship between immune alterations and MetS in patients with SZ, whilst controlling the impact of confounding clinical characteristics including psychiatric symptoms and comorbidities, history of childhood maltreatment and psychotropic treatments. Method: A total of 310 patients meeting DSM-IV criteria for SZ or schizoaffective disorders (SZA), with or without MetS, were systematically assessed and included in the FondaMental Advanced Centers of Expertise for Schizophrenia (FACE-SZ) cohort. Detailed clinical characteristics of patients, including psychotic symptomatology, psychiatric comorbidities and history of childhood maltreatment were recorded and the serum levels of 18 cytokines were measured. A penalized regression method was performed to analyze associations between inflammation and MetS, whilst controlling for confounding factors. Results: Of the total sample, 25% of patients had MetS. Eight cytokines were above the lower limit of detection (LLOD) in more than 90% of the samples and retained in downstream analysis. Using a conservative Variable Inclusion Probability (VIP) of 75%, we found that elevated levels of interleukin (IL)-6, IL-7, IL-12/23 p40 and IL-16 and lower levels of tumor necrosis factor (TNF)-α were associated with MetS. As for clinical variables, age, sex, body mass index (BMI), diagnosis of SZ (not SZA), age at the first episode of psychosis (FEP), alcohol abuse, current tobacco smoking, and treatment with antidepressants and anxiolytics were all associated with MetS. Conclusion: We have identified five cytokines associated with MetS in SZ suggesting that patients with psychotic disorders and MetS are characterized by a specific “immuno-metabolic” profile. This may help to design tailored treatments for this subgroup of patients with both psychotic disorders and MetS, taking one more step towards precision medicine in psychiatry. © 2022 The AuthorsImmuno-Génétique, Inflammation, retro-Virus, Environnement : de l'étiopathogénie des troubles psychotiques aux modèles animauxRéseau d'Innovation sur les Voies de Signalisation en Sciences de la Vi

CONTRIBUTION A L'ETUDE DE L'INFLUENCE DU DOPAGE SUR LES PROPRIETES ELECTRONIQUES DES CUPRATES SUPRACONDUCTEURS

In this work, we have investigated the phase diagram (T,p) through the effects of doping on the electronics properties of two systems La2-xSrxCuO4 and Bi2Sr2Ca1-xYxCu2-yZnyO8+d. First, the optical conductivity in two configurations, in-plane and out-of-plane, for two La2-xSrxCuO4 compounds (an under-doped with x = 0.08 and the optimally doped with x = 0.15) was analyzed. For under-doped case, along the c-axis and at low frequencies, we observed a decrease of the optical conductivity as temperature decreases. Moreover, with the in-plane configuration and at low frequencies, we have found a suppression of the scattering rate, which was accompanied by an increase of the effective mass when the temperature decreases. Since these results are only obtained in the under-doped one, they might be attributed to a signature of the pseudo-gap phase. In order to compare and to study the behavior of the Bi-2212 cuprate, we have synthesized Bi2Sr2Ca1-xYxCu2-yZnyO8+d samples. The yttrium substitution modifies the charge carriers concentration and the zinc substitution leads to a suppression of the superconductivity. At first, we have studied ceramics samples. Two ways of synthesis were used : the conventional solid-state reaction and the modified citrate process. The latter one has shown an improved purity and cristallinity. Transport measurements have shown that at high temperature, samples turn from a metallic state to a semi-conductive state upon the yttrium and zinc substitutions. We have grown Bi2Sr2Ca1-xYxCu2-yZnyO8+d crystals in an image furnace. The tests have shown that the growth is complex. After having optimized the parameters of the fusion on the un-doped composition, we have obtained single crystals with a typical size 15 x 5 x 0.2 mm3. For the substitutions, the yttrium prevents the growth of big crystals (i.e. the size could not exceed 3 x 1.5 x 0.2 mm3). The solubility limit of the zinc substitution on the copper site has been found to be equal to 0.03. Finally, we have grown and characterized single crystals with composition Bi1.99Sr2.01Ca0,76Y0.3Cu1.9Zn0.03O8+dDans ce mémoire, nous avons approché l'étude du diagramme de phase (T,p) des cuprates à travers l'étude des effets du dopage sur les propriétés électroniques de deux systèmes La2-xSrxCuO4 et Bi2Sr2Ca1-xYxCu2-yZnyO8+d. Dans un premier temps, la conductivité optique de deux échantillons La2-xSrxCuO4 a été analysée, dans les plans et perpendiculairement aux plans : un composé sous-dopé (x = 0,08) et le composé optimalement dopé (x = 0,15). Suivant l'axe c et à faibles fréquences, nous avons observé une diminution de la conductivité optique en diminuant la température pour l'échantillon sous-dopé. Dans les plans et pour le même composé, nous avons montré que le taux de diffusion diminuait et que la masse effective augmentait, lorsque la température diminue et à faibles fréquences. Puisque ces résultats ne sont obtenus que sur l'échantillon sous-dopé, ils peuvent correspondre à une signature de la phase de pseudo-gap. Dans le but de comparer et d'étudier le comportement du cuprate Bi-2212, nous avons synthétisé des échantillons de composition Bi2Sr2Ca1-xYxCu2-yZnyO8+d. La substitution à l'yttrium modifie la concentration des porteurs et la substitution au zinc conduit à la suppression de la supraconductivité. Nous avons d'abord analysé des échantillons céramiques. Deux voies d'élaboration ont été confrontées : la voie solide et la voie citrate modifiée. Cette dernière a montré une meilleure cristallinité et un caractère monophasé des poudres, caractéristiques importantes pour la croissance cristalline. Les mesures de transport ont montré que les céramiques évoluaient d'un régime métallique vers un comportement semi-conducteur, à haute température, en fonction de la substitution à l'yttrium mais également au zinc. Finalement, nous nous sommes intéressés à la croissance de monocristaux de Bi2Sr2Ca1-xYxCu2-yZnyO8+d dans un four à image. Les expériences ont montré que la croissance était délicate. Après avoir optimisé les paramètres de la fusion pour la composition non-dopée, nous avons fait croître des monocristaux de taille 15 x 5 x 0,2 mm3. Pour les substitutions, l'yttrium empêche la croissance de larges monocristaux qui n'excèdent pas la taille de 3 x 1,5 x 0,2 mm3. La limite de solubilité du zinc sur site cuivre a été définie à 0,03. A partir de ces résultats, des monocristaux de composition Bi1,99Sr2,01Ca0,76Y0,3Cu1,9Zn0,03O8+d ont été synthétisés et caractérisés

Is combination of UVC and H2O2 effective to remove estrogens from water?

International audienceWater pollution is of major concern in France. Half of water resources was still not meeting the European quality requirement in 2012. Moreover, recent progresses in analytical chemistry have identified numerous micropollutants in Wastewater Treatment Plant (WTP) discharge coming from urban, agricultural or industrial activities. Amongst hundreds of micropollutants, estrogenic compounds were shown to cause endocrine disruption in fish at very low doses [3] and suspected to impact human fertility [4]. Therefore, WTP upgrade is needed to eliminate these endocrine disruptors. Advanced oxidation processes were shown to eliminate up to 80% of targeted micropollutants [6]. However small and middle sized WTP (< 10000 equivalent inhabitants) are poorly equipped despite representing 90% of the overall French WTP [7]. Advanced Oxidation Processes (AOPs), based on the generation of highly reactive hydroxyl radicals for the unselective oxidation of chemical pollutants can be an adequate solution. This study aims at developing a cost-effective UV/H₂O₂ advance oxidation process (AOP) in order to reduce estrogenic activity in small and middle sized WTP discharge. Experiments were conducted at 20°C with a commercial UV reactor (COMAP WT) and a 55W low pressure lamp (Phillips) emitting at 254nm. Local tap water (Lyon, France) was added in a 50L glass tank and circulated at a flow rate of 40L/min in a closed system. A mixture of Estrone (E1), β-Estradiol (E2), and α-ethynyl estradiol (EE2) was added at 5µM and degradation rates were measured during either UV (photolysis) or UV + H₂O₂ treatments over 60min. Samples were taken every 10 minutes and analyzed by HPLC. Three different concentrations of H₂O₂ were tested: 10, 50 or 100mg/L. First results showed a low degradation of E2 and EE2 by photolysis after 60 min exposure (< 20%) in tap water but E1 was well degraded (up to 80%). When adding H₂O₂, every hormones degradation rate were significantly improved. Degradation rate reached 80% for E1 and 90% for E2 and EE2 at 10mg/L H₂0₂. Total degradation was both reached with 50mg/L and 100mg/L H₂0₂. These results pointed out that estrogens removal can be highly enhanced by combining UV and H₂O₂. Further investigations are needed to test this process on treated water at environmental concentrations

Comparison of UV/H2O2 and UV/S2O82- photolysis efficiency for the removal of estrogens in treated wastewater: chemical and biological assessment

International audienc

Temperature-triggered formation of a cellulose II nanocrystal network through regioselective derivatization

International audienceThe two ends of rodlike cellulose II nanocrystals (CNC-II) were regioselectively functionalized either with gold nanoparticles or thermosensitive polymer chains. In the first case, after the introduction of sulfur atoms at both ends of the rods, a labelling of CNC-II was carried out using a method based on the in situ nucleation and growth of gold nanoparticles (AuNP) from soluble derivatives. Transmission electron microscopy (TEM) images showed that such a method resulted in the grafting of one monodisperse AuNP at each extremity of the CNC-II, i.e. to the formation of hybrid dumbbell-shaped objects. No AuNP was detected on the lateral surfaces of the CNC-II and almost all observed CNC-II exhibited this dual labelling. This result confirmed with a good statistics when compared to previous works the possibility to derivatize only the two ends of the CNC-II, thanks to the antiparallel arrangement of cellulose chains in these nanoparticles. In the second case, the localized grafting of temperature-sensitive macromolecules onto the ends of the CNC-II was performed using an oxidation reaction followed by a peptide coupling. This end-specific grafting of thermosensitive chains onto CNC-II enhanced their colloidal stability when the temperature was below the lower critical solution temperature (LCST) of the polymer. Above the LCST, the TEM images revealed the formation of a network extending to tens of microns resulting from end-to-end associations of the derivatized rods through attractive interactions between collapsed polymer chains. Rheology experiments further evidenced a temperature-induced sol-gel transition from a liquid-like (sol) behavior below the LCST to solid-like (gel) behavior above the LCST, in agreement with a change from purely repulsive interactions to interconnections via the hydrophobic collapsed chains. Importantly, all results concur with a full reversibility of the phenomena upon cooling and reproducibility when samples were subjected to temperature cycles around the LCST. This work reveals that the dual sitespecific derivatization of CNC-II can provide symmetric hybrid particles with innovative assembling and macroscopic properties that cannot be obtained through homogenous chemical modifications

Magnetic properties of Ni(II)-Mn(III) LDHs

International audienceThe synthesis of Ni1−xMnx(OH)2(CO3)x/2*nH2O Layered Double Hydroxides (LDHs) for x = 0.2, 0.25 and 0.33, their characterisation by electron microscopy, X-ray diffraction and their magnetic properties are reported in this study. When x increases, the crystallinity of the nanoparticles is improved. The low temperature magnetic behaviour of these compounds is characteristic of the competition between in plane ferromagnetic and interlayer antiferromagnetic interactions. The ferromagnetism is due to in plane Ni cations interaction and decreases when manganese content increases (Tc decreases from 26 to 15 K when x increases from 0.2 to 0.33). It was found that the substitution of Ni by Mn ions favours the in plane antiferromagnetic order. This study demonstrates that magnetic interactions occur in LDH with non magnetic interlayer anions